Estimation of T2 relaxation time of breast cancer: Correlation with clinical, imaging and pathological features

Energy Technology Data Exchange (ETDEWEB)

Seo, Mirinae; Sohn, Yu Mee [Dept. of Radiology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul (Korea, Republic of); Ryu, Jung Kyu; Jahng, Geon Ho; Rhee, Sun Jung; Oh, Jang Hoon; Won, Kyu Yeoun [Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul (Korea, Republic of)

2017-01-15

The purpose of this study was to estimate the T2* relaxation time in breast cancer, and to evaluate the association between the T2* value with clinical-imaging-pathological features of breast cancer. Between January 2011 and July 2013, 107 consecutive women with 107 breast cancers underwent multi-echo T2*-weighted imaging on a 3T clinical magnetic resonance imaging system. The Student's t test and one-way analysis of variance were used to compare the T2* values of cancer for different groups, based on the clinical-imaging-pathological features. In addition, multiple linear regression analysis was performed to find independent predictive factors associated with the T2* values. Of the 107 breast cancers, 92 were invasive and 15 were ductal carcinoma in situ (DCIS). The mean T2* value of invasive cancers was significantly longer than that of DCIS (p = 0.029). Signal intensity on T2-weighted imaging (T2WI) and histologic grade of invasive breast cancers showed significant correlation with T2* relaxation time in univariate and multivariate analysis. Breast cancer groups with higher signal intensity on T2WI showed longer T2* relaxation time (p = 0.005). Cancer groups with higher histologic grade showed longer T2* relaxation time (p = 0.017). The T2* value is significantly longer in invasive cancer than in DCIS. In invasive cancers, T2* relaxation time is significantly longer in higher histologic grades and high signal intensity on T2WI. Based on these preliminary data, quantitative T2* mapping has the potential to be useful in the characterization of breast cancer.

Association of (C677T Gene Polymorphism with Breast Cancer in North India

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Mohammad Waseem

2016-01-01

Full Text Available Background Breast cancer is one of the most common malignancies in women and is associated with a variety of risk factors. The functional single-nucleotide polymorphism (SNP C677T in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR may lead to decreased enzyme activity and affect the chemosensitivity of tumor cells. This study was designed to investigate the association of MTHFR gene polymorphism (SNP in the pathogenesis of breast cancer among the North Indian women population. Materials and Methods Genotyping was performed by polymerase chain reaction (PCR using genomic DNA, extracted from the peripheral blood of subjects with (275 cases or without (275 controls breast cancer. Restriction fragment length polymorphism was used to study C677T polymorphism in the study groups. Results The distribution of MTHFR (C677T genotype frequencies, ie, CC, TT, and CT, among the patients was 64.7%, 2.18%, and 33.09%, respectively. In the healthy control group, the CC, TT, and CT frequencies were 78.91%, 1.09%, and 20.1%, respectively. The frequencies of C and T alleles were 81.2% and 18.7%, respectively, in the patient subjects, while they were 88.9% and 11.09%, respectively, among the healthy control group. Frequencies of the CT genotype and the T allele were significantly different ( P = 0.007 and P = 0.005, respectively between the control and the case subjects. Conclusion This study shows an association of the CT genotype and the T allele of the MTHFR (C667T gene with increased genetic risk for breast cancer among Indian women.

ESR1 single nucleotide polymorphism rs1062577 (c.*3804T>A) alters the susceptibility of breast cancer risk in Iranian population.

Science.gov (United States)

Dehghan, Zahra; Sadeghi, Samira; Tabatabaeian, Hossein; Ghaedi, Kamran; Azadeh, Mansoureh; Fazilati, Mohammad; Bagheri, Fatemeh

2017-05-05

Albeit single nucleotide polymorphisms related to ESR1 gene have been studied, only a number of them have been reported to be associated with breast cancer risk. rs1062577 is one of the most recent microRNA-related ESR1 SNPs; however, no study has been conducted to investigate the significance this polymorphism in Iranian population. In this study, we aimed to investigate the frequency and also the association between rs1062577 and breast cancer. rs1062577 position was genotyped by Tetra-primer ARMS-PCR in totally 182 blood specimens obtained from breast cancer patients (n=86), and healthy blood donors (n=96). The distribution of different genotypes was statistically analyzed in terms of the potential association between rs1062577 different alleles, breast cancer risk and clinicopathological criteria of breast cancer patients. The statistical analyses confidently indicated that rs1062577 A allele is associated with the increased breast cancer risk in both univariate and multivariate regression models (Odds Ratio=8.403 and 32.602 respectively). rs1062577 T allele was statistically associated with stage I of breast cancer patients (p-value=0.025). In silico studies implied that rs1062577 A allele can alter the binding capacity of ESR1 mRNA and miRNAs via either breakage or formation of hydrogen bonds. rs1062577 A allele is significantly and dramatically associated with the elevated risk and greater stages of breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficacy of breast conservation therapy in early stage bilateral breast cancer

International Nuclear Information System (INIS)

Lee, Misa M.; Chen, Luci M.; Heimann, Ruth; Powers, Claire; Weichselbaum, Ralph R.

1996-01-01

PURPOSE: To evaluate outcome of patients with bilateral breast cancer as compared to unilateral breast cancer treated with breast conservation therapy. This is a complex issue, however, we address this by comparing (1) synchronous bilateral breast cancer patients, (2) metachronous bilateral breast cancer patients from the time of diagnosis of the second breast primary, and (3) unilateral breast cancer patients. The authors recognize that there are inherent biases in these comparisons. MATERIALS AND METHODS: A total of 60 bilateral patients and 1080 unilateral patients treated with breast conservation therapy from 1977-1994 were analyzed for outcome. Of the 60 bilateral patients, 44 were metachronous bilateral breast cancer patients (MBBC) and 16 were synchronous breast cancer patients (SBBC). Patients with bilateral breast cancer had local-regional disease with the following tumor stages: DCIS=8%, T1=80%, T2=12%, pathologic N0=90%, pathologic N+=10%. Unilateral patients had the following tumor stages: DCIS=10%, T1=66%, T2=20%, T3=1.2%, Tx=2%, pathological N0=80%, pathological N+=19%, and NX=1%. The majority of patients received lumpectomy and axillary node dissection followed by radiation therapy. The median size of the lesions were 1.4cm and 1.5cm for bilateral and unilateral patients, respectively. Median total dose to the primary tumor was 60Gy for both unilateral and bilateral patients. Of the 44 metachronous bilateral breast cancer patients, 14 patients received breast conservation for both the first and second lesions while 30 patients had breast conservation for only the second metachronous breast lesion. Thus 58 lesions in the 44 patients were treated with breast conservation therapy in the patients with metachronous bilateral breast cancer. Of the synchronous bilateral breast cancer patients, 13 out of 16 patients had breast conserving therapy for both breasts, and 3 patients received mastectomy for the second synchronous breast tumor. The median follow

Analysis of 6174delT Mutation in BRCA2 Gene by Mutagenically Separated PCR Among Libyan Patients with Breast Cancer

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Lamia Elfandi

2016-03-01

Full Text Available Background: Breast cancer is the most common malignancy among women. It is estimated that 1 in 10 women worldwide is affected by breast cancer during their lifetime. In 5 to 10% of breast cancer patients, the disease results from a hereditary predisposition, which can be attributable to mutations in either of two tumor suppressor genes, BRCA1 and BRCA2 to a large extent. BRCA2 6174delT mutation constitutes the common mutant alleles which predispose to hereditary breast cancer in the Ashkenazi population with a reported carrier frequency of 1.52%. In this study, we investigated the presence of the 6174delT mutation of the BRCA2 gene in Libyan woman affected with breast cancer and compared the results with those of other population groups.Methods: Eighty- five Libyan women with breast cancer in additions to 5 relatives of the patients (healthy individuals were recruited to this study. We obtained clinical information, family history, and peripheral blood for DNA extraction and analyzed the data using multiplex mutagenic polymerase chain reaction (MS-PCR for detection of 6174delT mutation in the BRCA2 gene. Results: The 6174delT of the BRCA2 gene was not detected either in the 85 patients with breast cancer (18 with familial breast cancer and 67 with sporadic breast cancer nor in the 5 healthy individuals. Conclusions: The present study showed that the 6174delT of the BRCA2 gene was not detectable using mutagenic PCR in the Libyan patients with breast cancer and can be considered to be exceedingly rare

Inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer

Institute of Scientific and Technical Information of China (English)

Zhao Li; Ma Yongjie; Gu Feng; Fu Li

2014-01-01

Background Paclitaxel (PAC) is the first-line chemotherapy drug for most breast cancer patients,but clinical studies showed that some breast cancer patients were insensitive to PAC,which led to chemotherapy failure.It was reported that Notch1 signaling participated in drug resistance of breast cancer.Here,we show whether Notch1 expression is related to PAC sensitivity of breast cancer.Methods We employed Notch1 siRNA and Notch1 inhibitor,N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT),to down regulate Notch1 expression in human breast cancer cells MDA-MB-231,and detected the inhibition effect by Western blotting and reverse trans cription-polymerase chain reaction,respectively.After 24 hours exposure to different concentration of PAC (0,1,5,10,15,20,and 25 μg/ml),the viability of the control group and experimental group cells was tested by MTT.We also examined the expression of Notch1 in PAC sensitive and nonsensitive breast cancer patients,respectively by immunohistochemistry (IHC).The PAC sensitivity of breast cancer patients were identified by collagen gel droplet embedded culture-drug sensitivity test (CD-DST).Results Down regulation of Notch1 expression by Notch1siRNA interference or Notch1 inhibitor increased the PAC sensitivity in MDA-MB-231 cells (P ＜0.05).Also,the expression of Notch1 in PAC sensitive patients was much lower than that of PAC non-sensitive patients (P ＜0.01).Conclusion Notch1 expression has an effect on PAC sensitivity in breast cancer patients,and the inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.

BRCA1/2 associated hereditary breast cancer

Institute of Scientific and Technical Information of China (English)

Li-song TENG; Yi ZHENG; Hao-hao WANG

2008-01-01

Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

Immodin and its immune system supportive role in paclitaxel therapy of 4T1 mouse breast cancer.

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Demečková, Vlasta; Solár, Peter; Hrčková, Gabriela; Mudroňová, Dagmar; Bojková, Bianka; Kassayová, Monika; Gancarčiková, Soňa

2017-05-01

It is evident that standard chemotherapy agents may have an impact on both tumor and host immune system. Paclitaxel (PTX), a very potent anticancer drug from a taxane family, has achieved prominence in clinical oncology for its efficacy against a wide range of tumors including breast cancer. However, significant toxicity, such as myelosuppression, limit the effectiveness of Paclitaxel-based treatment regimens. Immodin (IM) is low molecular dialysate fraction of homogenate made from human leukocytes. It contains a mixture of substances from which so far have been described e.g. Imreg 1 and Imreg 2 formed by the dipeptide tyrosine-glycine and the tripeptide tyrosine-glycine-glycine, respectively. The aim of this study was to explore immunopharmacological activities of IM, using the strongly immunogenic 4T1 mouse breast cancer model, and evaluate its effect on the reactivity and the efficiency of PTX cancer therapy. The results highlight a potentially beneficial role for IM in alleviating PTX-induced toxicity, especially on the nonspecific immunity, during breast cancer therapy. Co-treatment exhibited an antitumor effect including reduced tumor growth, prolonged survival of tumor bearing mice, increased number of monocytes and lymphocytes in peripheral blood. In spleens, IM+PTX therapy elevated proportion of whole lymphocytes in the account of myelo-monocytic cells characteristic with low expression of CD11c+ and bearing Fc receptor (CD16/32) as well as T-lymphocytes, NK cells and dendritic cells. Accumulation of tumor-associated granulocytes in stroma of PTX-treated group and intensive 4T1-necrosis/apoptosis in tumors after co-treatment were also recorded. These findings suggest the possibility of using IM alongside PTX treatment for maintaining the immune system functions and increasing patient survival. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development

Science.gov (United States)

Aspord, Caroline; Pedroza-Gonzalez, Alexander; Gallegos, Mike; Tindle, Sasha; Burton, Elizabeth C.; Su, Dan; Marches, Florentina; Banchereau, Jacques; Palucka, A. Karolina

2007-01-01

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development. PMID:17438063

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

Science.gov (United States)

Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C; Hansen, Thomas Vo; Osorio, Ana; Benitez, Javier; Conejero, Raquel Andrés; Segota, Ena; Weitzel, Jeffrey N; Thelander, Margo; Peterlongo, Paolo; Radice, Paolo; Pensotti, Valeria; Dolcetti, Riccardo; Bonanni, Bernardo; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Manoukian, Siranoush; Varesco, Liliana; Capone, Gabriele L; Papi, Laura; Ottini, Laura; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brady, Angela; Brewer, Carole; Foo, Claire; Evans, D Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Cook, Jackie; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M John; Tischkowitz, Marc; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Cole, Trevor; Godwin, Andrew K; Isaacs, Claudine; Claes, Kathleen; De Leeneer, Kim; Meindl, Alfons; Gehrig, Andrea; Wappenschmidt, Barbara; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Schmutzler, Rita K; Preisler-Adams, Sabine; Markov, Nadja Bogdanova; Wang-Gohrke, Shan; de Pauw, Antoine; Lefol, Cédrick; Lasset, Christine; Leroux, Dominique; Rouleau, Etienne; Damiola, Francesca; Dreyfus, Hélène; Barjhoux, Laure; Golmard, Lisa; Uhrhammer, Nancy; Bonadona, Valérie; Sornin, Valérie; Bignon, Yves-Jean; Carter, Jonathan; Van Le, Linda; Piedmonte, Marion; DiSilvestro, Paul A; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Aittomäki, Kristiina; Jager, Agnes; van den Ouweland, Ans Mw; Kets, Carolien M; Aalfs, Cora M; van Leeuwen, Flora E; Hogervorst, Frans Bl; Meijers-Heijboer, Hanne Ej; Oosterwijk, Jan C; van Roozendaal, Kees Ep; Rookus, Matti A; Devilee, Peter; van der Luijt, Rob B; Olah, Edith; Diez, Orland; Teulé, Alex; Lazaro, Conxi; Blanco, Ignacio; Del Valle, Jesús; Jakubowska, Anna; Sukiennicki, Grzegorz; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Agnarsson, Bjarni A; Maugard, Christine; Amadori, Alberto; Montagna, Marco; Teixeira, Manuel R; Spurdle, Amanda B; Foulkes, William; Olswold, Curtis; Lindor, Noralane M; Pankratz, Vernon S; Szabo, Csilla I; Lincoln, Anne; Jacobs, Lauren; Corines, Marina; Robson, Mark; Vijai, Joseph; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Mulligan, Anna Marie; Glendon, Gord; Andrulis, Irene L; Tchatchou, Sandrine; Toland, Amanda Ewart; Pedersen, Inge Sokilde; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe Birk; Caligo, Maria A; Friedman, Eitan; Zidan, Jamal; Laitman, Yael; Lindblom, Annika; Melin, Beatrice; Arver, Brita; Loman, Niklas; Rosenquist, Richard; Olopade, Olufunmilayo I; Nussbaum, Robert L; Ramus, Susan J; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Lester, Jenny; Orsulic, Sandra; Stoppa-Lyonnet, Dominique; Thomas, Gilles; Simard, Jacques; Couch, Fergus J; Offit, Kenneth; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Mazoyer, Sylvie; Phelan, Catherine M; Sinilnikova, Olga M; Cox, David G

2015-04-25

Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Coping with uncertainty: T1a,bN0M0 HER2-positive breast cancer, do we have a treatment threshold?

LENUS (Irish Health Repository)

Kelly, C M

2012-02-01

BACKGROUND: Recent retrospective studies have suggested that patients with T1a,bN0M0 human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a higher risk for recurrence and might benefit from adjuvant trastuzumab. The absolute benefits associated with treating this subgroup are uncertain. Design: We reviewed recent studies examining the prognostic value of HER2 in patients with node-negative T1a,b HER2-positive breast cancer. We calculated the number needed to treat (NNT) using baseline risk estimates for untreated T1a,bN0M0 breast cancer and the number needed to harm (NNH) using the incidence of cardiac events in each of the adjuvant trastuzumab clinical trials. RESULTS: Several studies were identified, each with limitations inherent to retrospective database analyses: small cohort sizes, lack of systematic HER2 testing in older specimens, variations in the use of adjuvant therapy and definitions of study end points, and lack of information relating to comorbidities. The 5-year disease-free survival in the pre-trastuzumab era ranged from 77% to 95%. Comparisons between small HER2 -positive and small HER2 -negative cancers showed numerically worse outcome for the HER2-positive cohort in some but not all studies. In many instances, the NNH was larger (26-250) than the NNT (13-35); however, in a subset of patients, the NNH was lower (6) than the NNT (13-35). CONCLUSIONS: Better prediction tools to estimate more precisely the risk for death due to comorbid illness versus breast cancer are needed. In some patients, the risks of therapy could outweigh the benefits. Treatment selection for T1a,bN0 HER2-positive cancers remains in the transition area between evidence- and subjective judgment-based medicine.

Reprogramming tumor-infiltrating dendritic cells for CD103+CD8+ mucosal T cell differentiation and breast cancer rejection

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Wu, Te-Chia; Xu, Kangling; Banchereau, Romain; Marches, Florentina; Yu, Chun I; Martinek, Jan; Anguiano, Esperanza; Pedroza-Gonzalez, Alexander; Snipes, G. Jackson; O’Shaughnessy, Joyce; Nishimura, Stephen; Liu, Yong-Jun; Pascual, Virginia; Banchereau, Jacques; Oh, Sangkon; Palucka, Karolina

2014-01-01

Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory T helper 2 (iTh2) cells and protumor inflammation. Here we show that intratumoral delivery of the β-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells, and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DC via the ligation of dectin-1, enabling the DC to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL12p70, and to favor the generation of T helper 1 (Th1) cells. DC activated via dectin-1, but not those activated with TLR-7/8 ligand or poly IC, induce CD8+ T cells to express CD103 (αE integrin), a ligand for cancer cells E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC-derived integrin αvβ8 and TGF-β activation in a dectin-1-dependent fashion. These CD103+CD8+ mucosal T cells accumulate in the tumors thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+CD8+ mucosal T cells elicited by reprogrammed DC can reject established cancer. Thus, reprogramming tumor-infiltrating DC represents a new strategy for cancer rejection. PMID:24795361

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium.

Science.gov (United States)

Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo; Jakubowska, Anna; Heikkilä, Päivi; Fagerholm, Rainer; Greco, Dario; Aittomäki, Kristiina; Bojesen, Stig E; Shah, Mitul; Dunning, Alison M; Rhenius, Valerie; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Chang-Claude, Jenny; Rudolph, Anja; Nordestgaard, Børge G; Couch, Fergus J; Hart, Steven N; Figueroa, Jonine; García-Closas, Montserrat; Fasching, Peter A; Beckmann, Matthias W; Li, Jingmei; Liu, Jianjun; Andrulis, Irene L; Winqvist, Robert; Pylkäs, Katri; Mannermaa, Arto; Kataja, Vesa; Lindblom, Annika; Margolin, Sara; Lubinski, Jan; Dubrowinskaja, Natalia; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F; Pharoah, Paul D P; Schmidt, Marjanka K; Nevanlinna, Heli

2016-10-03

P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly

BP1 Homeoprotein Enhances Metastatic Potential in ER-negative Breast Cancer

Science.gov (United States)

Fu, Yebo; Lian, Yi; Kim, Kyung Soon; Zhang, Lei; Hindle, A. Katharine; Brody, Fred; Siegel, Robert S.; McCaffrey, Timothy A.; Fu, Sidney W.

2010-01-01

Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER-) tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. We sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p=2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Significant pathways were identified involving cell proliferation and metastasis. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target for ER- breast cancer. PMID:20842225

Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt overexpression

International Nuclear Information System (INIS)

Wang, Kuo; Cao, Fang; Fang, Wenzheng; Hu, Yongwei; Chen, Ying; Ding, Houzhong; Yu, Guanzhen

2013-01-01

SNAT1 is a subtype of the amino acid transport system A that has been implicated to play a potential role in cancer development and progression, yet its role in breast cancer remains unclear. In present study, we detected SNAT1 expression in breast cancers and explored its underlying mechanism in promoting breast carcinogenesis. RT-PCR and Western blotting were performed to analyze the transcription and protein levels of SNAT1 in breast cancer cell lines and fresh tissues. Tissue microarray blocks containing breast cancer specimens obtained from 210 patients were constructed. Expression of SNAT1 in these specimens was analyzed using immunohistochemical studies. SNAT1 was down-regulated by SNAT1-shRNA in breast cancer cells and the functional significance was measured. SNAT1 was up-regulated in breast cancer cell lines and breast cancer tissues. Overexpression of SNAT1 was observed in 127 cases (60.5%). Expression of SNAT1 was significantly associated with tumor size, nodal metastasis, advanced disease stage, Ki-67, and ER status. Suppression of endogenous SNAT1 leads to cell growth inhibition, cell cycle arrest, and apoptosis of 4T1 cells and lowered the phosphorylation level of Akt. SNAT1 expression correlated significantly with p-Akt expression in human breast cancer samples. The cross-talk between Akt signaling and SNAT1 might play a critical role in the development and progression of breast cancer, providing an important molecular basis for novel diagnostic markers and new attractive targets in the treatment of breast cancer patients

T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

Science.gov (United States)

Beausang, John F; Wheeler, Amanda J; Chan, Natalie H; Hanft, Violet R; Dirbas, Frederick M; Jeffrey, Stefanie S; Quake, Stephen R

2017-11-28

Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. Copyright © 2017 the Author(s). Published by PNAS.

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

Institute of Scientific and Technical Information of China (English)

Shicheng Su; Ling Lin; Yunjie Zeng; Nengtai Ouyang; Xiuying Cui; Herui Yao; Fengxi Su; Jian-dong Huang; Judy Lieberman; Qiang Liu; Erwei Song; Jianyou Liao; Jiang Liu; Di Huang; Chonghua He; Fei Chen; LinBing Yang; Wei Wu; Jianing Chen

2017-01-01

The origin of tumor-infiltrating Tregs,critical mediators of tumor immunosuppression,is unclear.Here,we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires,while hardly overlap with circulating Tregs,suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs.Furthermore,the abundance of naive CD4+ T cells and Tregs is closely correlated,both indicating poor prognosis for breast cancer patients.Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCLl8-producing macrophages.Moreover,adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner.In human breast cancer xenografts in humanized mice,blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3,a CCL18 receptor,significantly reduces intratumoral Tregs and inhibits tumor progression.These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ.Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

Science.gov (United States)

Su, Shicheng; Liao, Jianyou; Liu, Jiang; Huang, Di; He, Chonghua; Chen, Fei; Yang, LinBing; Wu, Wei; Chen, Jianing; Lin, Ling; Zeng, Yunjie; Ouyang, Nengtai; Cui, Xiuying; Yao, Herui; Su, Fengxi; Huang, Jian-dong; Lieberman, Judy; Liu, Qiang; Song, Erwei

2017-01-01

The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy. PMID:28290464

Role of KCNMA1 in breast cancer.

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Martin Oeggerli

Full Text Available KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca(2+-activated (BK potassium channel and has been reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fraction of breast, ovarian and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3-7%. We performed an extensive analysis on breast cancer tissue microarrays (TMA of 1,200 tumors linked to prognosis. KCNMA1 amplification was significantly associated with high tumor stage, high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 protein expression in 8 out of 9 human breast cancers and in the breast cancer cell line MFM223. KCNMA1-function in breast cancer cell lines was confirmed by whole-cell patch clamp recordings and proliferation assays, using siRNA-knockdown, BK channel activators such as 17ß-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expression of KCNMA1 correlates with and contributes to high proliferation rate and malignancy of breast cancer.

T cells reactive with HLA-A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients.

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Coleman, Julia A; Correa, Isabel; Cooper, Lucienne; Bohnenkamp, Hermann R; Poulsom, Richard; Burchell, Joy M; Taylor-Papadimitriou, Joyce

2011-05-01

The nuclear protein PLU-1/JARID1B/KDM5 is widely expressed in breast cancers while showing highly restricted expression in normal adult tissues. To investigate whether JARID1B is a potential target antigen for immunotherapy of breast cancer, we have analyzed the responses of CD8(+) T cells to JARID1B HLA-A*0201 peptides in vitro and used peptide multimers to detect the presence of JARID1B reactive T cells in the circulation of breast cancer patients. Peptides were selected using two web-based algorithms: criteria for inclusion being a high score in both prediction algorithms, and nonhomology with retinoblastoma binding protein-2 (RBP2/JARID1A/KDM5A). A 65-peptide panel was selected and assayed for binding strength by competition assay to obtain the IC(50). The immunogenicity in vitro of these peptides was assessed by T cell stimulation experiments, using autologous dendritic cells as APCs in the first rounds followed by autologous lymphoblasts. Fourteen of the peptides assayed produced cultures having >2% of the CD8(+) cells being IFN-γ(+) after 3-6 rounds of stimulation. An HLA-A*0201 cell line could activate the specific T cells if pulsed with peptide, but endogenous peptide levels were insufficient for activation. Nevertheless, multimer staining of circulating T cells from breast cancer patients showed a significantly higher percentage of multimer positive CD8(+) T cells, as compared to healthy adults for two of three JARID1B epitopes tested. One of these, peptide 73 (QLYALPCVL), was analyzed for memory phenotype, and found to have a significantly higher proportion of central memory T cells than the control group, demonstrating a previous exposure to the peptide. Copyright © 2011 UICC.

Nanopulse Stimulation (NPS Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

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Stephen J. Beebe

2018-03-01

Full Text Available Nanopulse Stimulation (NPS eliminates mouse and rat tumor types in several different animal models. NPS induces protective, vaccine-like effects after ablation of orthotopic rat N1-S1 hepatocellular carcinoma. Here we review some general concepts of NPS in the context of studies with mouse metastatic 4T1 mammary cancer showing that the postablation, vaccine-like effect is initiated by dynamic, multilayered immune mechanisms. NPS eliminates primary 4T1 tumors by inducing immunogenic, caspase-independent programmed cell death (PCD. With lower electric fields, like those peripheral to the primary treatment zone, NPS can activate dendritic cells (DCs. The activation of DCs by dead/dying cells leads to increases in memory effector and central memory T-lymphocytes in the blood and spleen. NPS also eliminates immunosuppressive cells in the tumor microenvironment and blood. Finally, NPS treatment of 4T1 breast cancer exhibits an abscopal effect and largely prevents spontaneous metastases to distant organs. NPS with fast rise–fall times and pulse durations near the plasma membrane charging time constant, which exhibits transient, high-frequency components (1/time = Hz, induce responses from mitochondria, endoplasmic reticulum, and nucleus. Such effects may be responsible for release of danger-associated molecular patterns, including ATP, calreticulin, and high mobility group box 1 (HMBG1 from 4T1-Luc cells to induce immunogenic cell death (ICD. This likely leads to immunity and the vaccine-like response. In this way, NPS acts as a unique onco-immunotherapy providing distinct therapeutic advantages showing possible clinical utility for breast cancers as well as for other malignancies.

Radiation Use and Long-Term Survival in Breast Cancer Patients With T1, T2 Primary Tumors and One to Three Positive Axillary Lymph Nodes

International Nuclear Information System (INIS)

Buchholz, Thomas A.; Woodward, Wendy A.; Duan Zhigang; Fang Shenying; Oh, Julia L.; Tereffe, Welela; Strom, Eric A.; Perkins, George H.; Yu, T.-K.; Hunt, Kelly K.; Meric-Bernstam, Funda; Hortobagyi, Gabriel N.; Giordano, Sharon H.

2008-01-01

Background: For patients with Stage II breast cancer with one to three positive lymph nodes, controversy exists about whether radiation as a component of treatment provides a survival benefit. Methods and Materials: We analyzed data from patients with Stage II breast cancer with one to three positive lymph nodes diagnosed from 1988-2002 in the Surveillance, Epidemiology, and End Results registry and compared the outcome of 12,693 patients treated with breast-conservation therapy with radiation (BCT + XRT) with the 18,902 patients treated with mastectomy without radiation (MRM w/o XRT). Results: Patients treated with BCT + XRT were younger, were more likely to be treated in recent years of the study period, more commonly had T1 primary tumors, and had fewer involved nodes compared with those treated with MRM w/o XRT (p < 0.001 for all differences). The 15-year breast cancer-specific survival rate for the BCT + XRT group was 80% vs. 72% for the MRM w/o XRT group (p < 0.001). Cox regression analysis showed that MRM w/o XRT was associated with a hazard ratio for breast cancer death of 1.19 (p < 0.001) and for overall death of 1.25 (p < 0.001). The survival benefit in the BCT + XRT group was not limited to subgroups with high-risk disease features. Conclusions: Radiation use was independently associated with improved survival for patients with Stage II breast cancer with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials

Mammographic features of screening detected pT1 (a–b) invasive breast cancer using BI-RADS lexicon

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Bargalló, Xavier, E-mail: xbarga@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Santamaría, Gorane, E-mail: gsanta@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Velasco, Martín, E-mail: mvelasco@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Amo, Montse del, E-mail: mdelamo@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Arguis, Pedro, E-mail: parguis@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Burrel, Marta, E-mail: mburrel@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain); Capurro, Sebastian, E-mail: scapurro@clinic.ub.es [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona (Spain)

2012-10-15

Aim: To describe mammographic features in screening detected invasive breast cancer less than or equal to 10 mm using Breast Imaging Reporting and Data System lexicon in full-field digital mammography. Patients and methods: A retrospective analysis of 123 pT1 (a–b) invasive breast cancers in women aged 50–69 years from our screening program. Radiologic patterns were: masses, calcifications, distortions, asymmetries and mixed. Masses: shape, margins and density, and calcifications: morphology, number of flecks and size of the cluster were taken into account, following Breast Imaging Reporting and Data System terminology. Results: We found 61 masses (49.6%), 8 masses with calcifications (6.5%), 30 groups of calcifications (24.4%), 19 architectural distortions (15.4%), 1 architectural distortion with calcifications (0.8%), 4 asymmetries (3.2%). Sixty out of 69 masses were irregular in shape, 6 lobular, 2 ovals and 1 round. Thirty-four showed ill-defined margins, 29 spiculated and 6 microlobulated. Most of them showed a density similar to surrounding fibroglandular tissue. Calcifications were pleomorphic or fine linear in 24 of 30 (80%). Most of cases showed more than 10 flecks and a size greater than 1 cm. Conclusion: The predominant radiologic finding is an irregular, isodense mass those margins tend to share different descriptors, being ill-defined margins the most constant finding. Calcifications representing invasive cancer are predominantly pleomorphic with more than 10 flecks per cm. Architectural distortion and invasive tubular carcinoma are more common than reported in general series.

Mammographic features of screening detected pT1 (a–b) invasive breast cancer using BI-RADS lexicon

International Nuclear Information System (INIS)

Bargalló, Xavier; Santamaría, Gorane; Velasco, Martín; Amo, Montse del; Arguis, Pedro; Burrel, Marta; Capurro, Sebastian

2012-01-01

Aim: To describe mammographic features in screening detected invasive breast cancer less than or equal to 10 mm using Breast Imaging Reporting and Data System lexicon in full-field digital mammography. Patients and methods: A retrospective analysis of 123 pT1 (a–b) invasive breast cancers in women aged 50–69 years from our screening program. Radiologic patterns were: masses, calcifications, distortions, asymmetries and mixed. Masses: shape, margins and density, and calcifications: morphology, number of flecks and size of the cluster were taken into account, following Breast Imaging Reporting and Data System terminology. Results: We found 61 masses (49.6%), 8 masses with calcifications (6.5%), 30 groups of calcifications (24.4%), 19 architectural distortions (15.4%), 1 architectural distortion with calcifications (0.8%), 4 asymmetries (3.2%). Sixty out of 69 masses were irregular in shape, 6 lobular, 2 ovals and 1 round. Thirty-four showed ill-defined margins, 29 spiculated and 6 microlobulated. Most of them showed a density similar to surrounding fibroglandular tissue. Calcifications were pleomorphic or fine linear in 24 of 30 (80%). Most of cases showed more than 10 flecks and a size greater than 1 cm. Conclusion: The predominant radiologic finding is an irregular, isodense mass those margins tend to share different descriptors, being ill-defined margins the most constant finding. Calcifications representing invasive cancer are predominantly pleomorphic with more than 10 flecks per cm. Architectural distortion and invasive tubular carcinoma are more common than reported in general series

Method of localization and implantation of the lumpectomy site for high dose rate brachytherapy after conservative surgery for T1 and T2 breast cancer

International Nuclear Information System (INIS)

Perera, F.; Chisela, F.; Engel, J.; Venkatesan, V.

1995-01-01

Purpose: This article describes our technique of localization and implantation of the lumpectomy site of patients with T1 and T2 breast cancer. Our method was developed as part of our Phase I/II pilot study of high dose rate (HDR) brachytherapy alone after conservative surgery for early breast cancer. Methods and Materials: In March 1992, we started a pilot study of HDR brachytherapy to the lumpectomy site as the sole radiotherapy after conservative surgery for clinical T1 or T2 invasive breast cancer. Initially, the protocol required intraoperative placement of the interstitial needles at the time of definitive surgery to the breast. The protocol was then generalized to allow the implantation of the lumpectomy site after definitive surgery to the breast, either at the time of subsequent axillary nodal dissection or postoperatively. To date, five patients have been implanted intraoperatively at the time of definitive breast surgery. Twelve patients were implanted after definitive breast surgery, with 7 patients being done at the time of axillary nodal dissection and 5 patients postoperatively. We devised a method of accurately localizing and implanting the lumpectomy site after definitive breast surgery. The method relies on the previous placement of surgical clips by the referring surgeon to mark the lumpectomy site. For each patient, a breast mold is made with radio-opaque angiocatheters taped onto the mold in the supero-inferior direction. A planning CT scan is then obtained through the lumpectomy site. The volume of the lumpectomy site, the number of implant planes necessary, and the orientation of the implants are then determined from the CT scan. The angiocatheters provide a reference grid on the CT films to locate the entry and exit points of the interstitial needles on the plastic mold. The entry and exit points for reference needles are then transferred onto the patient's skin enabling implantation of the lumpectomy site. Needle positions with respect to

Male Breast Cancer

Science.gov (United States)

Although breast cancer is much more common in women, men can get it too. It happens most often to men between ... 60 and 70. Breast lumps usually aren't cancer. However, most men with breast cancer have lumps. ...

Specificity of choline metabolites for in vivo diagnosis of breast cancer using 1H MRS at 1.5 T

International Nuclear Information System (INIS)

Stanwell, Peter; Gluch, Laurence; Lean, Cynthia; Malycha, Peter; Mountford, Carolyn; Clark, David; Tomanek, Boguslaw; Baker, Luke; Giuffre, Bruno

2005-01-01

The purpose was to determine if in vivo proton magnetic resonance spectroscopy ( 1 H MRS) at 1.5 T can accurately provide the correct pathology of breast disease. Forty-three asymptomatic volunteers including three lactating mothers were examined and compared with 21 breast cancer patients. Examinations were undertaken at 1.5 T using a purpose-built transmit-receive single breast coil. Single voxel spectroscopy was undertaken using echo times of 135 and 350 ms. The broad composite resonance at 3.2 ppm, which includes contributions from choline, phosphocholine (PC), glycerophosphocholine (GPC), myo-inositol and taurine, was found not to be a unique marker for malignancy providing a diagnostic sensitivity and specificity of 80.0 and 86.0%, respectively. This was due to three of the asymptomatic volunteers and all of the lactating mothers also generating the broad composite resonance at 3.2 ppm. Optimised post-acquisitional processing of the spectra resolved a resonance at 3.22 ppm, consistent with PC, in patients with cancer. In contrast the spectra recorded for three false-positive volunteers, and the three lactating mothers had a resonance centred at 3.28 ppm (possibly taurine, myo-inositol or GPC). This improved the specificity of the test to 100%. Careful referencing of the spectra and post-acquisitional processing intended to optimise spectral resolution of in vivo MR proton spectra from human breast tissue resolves the composite choline resonance. This allows the distinction of patients with malignant disease from volunteers with a sensitivity of 80% and specificity of 100%. Therefore, resolution of the composite choline resonance into its constituent components improves the specificity of the in vivo 1 H MRS method, but does not overcome the problem of 20% false-negatives. (orig.)

Genetic variation in DNA repair gene XRCC7 (G6721T) and susceptibility to breast cancer.

Science.gov (United States)

Nasiri, Meysam; Saadat, Iraj; Omidvari, Shahpour; Saadat, Mostafa

2012-08-15

The human XRCC7 is a DNA double-strand break (DSBs) repair gene, involved in non-homologous end joining (NHEJ). It is speculated that DNA DSBs repair have an important role during development of breast cancer. The human XRCC7 is a NHEJ DSBs repair gene. Genetic variation G6721T of XRCC7 (rs7003908) is located in the intron 8 of the gene. This polymorphism may regulate splicing and cause mRNA instability. In the present study, we specifically investigated whether common G6721T genetic variant of XRCC7 was associated with an altered risk of breast cancer. The present study included 362 females with breast cancer. Age frequency-matched controls (362 persons) were randomly selected from the healthy female blood donors, according to the age distribution of the cases. Using RFLP-PCR based method, the polymorphism of XRCC7 was determined. The TG (OR=1.20, 95% CI: 0.83-1.74, P=0.320) and TT (OR=1.01, 95% CI: 0.67-1.53, P=0.933) genotypes had no significant effect on risk of breast cancer, in comparison with the GG genotype. Our present findings indicate that the TT and TG genotypes were not associated with an altered breast cancer risk. Copyright © 2012 Elsevier B.V. All rights reserved.

Postmastectomy radiotherapy improves disease-free survival of high risk of locoregional recurrence breast cancer patients with T1-2 and 1 to 3 positive nodes.

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Zhen-Yu He

Full Text Available The indications for post-mastectomy radiotherapy (PMRT with T1-2 breast cancer and 1-3 positive axillary lymph nodes is still controversial. The purpose of this study was to investigate the role of PMRT in T1-2 breast cancer with 1-3 positive axillary lymph node.We retrospectively reviewed the file records of 79 patients receiving PMRT and not receiving PMRT (618 patients.The median follow-up was 65 months. Multivariate analysis showed that PMRT was an independent prognostic factor of locoregional recurrence-free survival (LRFS (P = 0.010. Subgroup analysis of patients who did not undergo PMRT showed that pT stage, number of positive axillary lymph nodes, and molecular subtype were independent prognostic factors of LRFS. PMRT improved LRFS in the entire group (P = 0.005, but did not affect distant metastasis-free survival (DMFS (P = 0.494, disease-free survival (DFS (P = 0.215, and overall survival (OS (P = 0.645. For patients without PMRT, the 5-year LRFS of low-risk patients (0-1 risk factor for locoregional recurrence of 94.5% was significantly higher than that of high-risk patients (2-3 risk factors for locoregional recurrence (80.9%, P < 0.001. PMRT improved LRFS (P = 0.001 and DFS (P = 0.027 in high-risk patients, but did not improve LRFS, DMFS, DFS, and OS in low-risk patients.PMRT is beneficial in patients with high risk of locoregional recurrence breast cancer patients with T1-2 and 1 to 3 positive nodes.

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

DEFF Research Database (Denmark)

Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo

2016-01-01

BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival...... and characteristics of breast tumors of germ line p.I157T carriers. METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer...... characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models...

CYP1B1 expression, a potential risk factor for breast cancer

Energy Technology Data Exchange (ETDEWEB)

Goth-Goldstein, Regine; Erdmann, Christine A.; Russell, Marion

2001-05-31

CYP1B1 expression in non-tumor breast tissue from breast cancer patients and cancer-free individuals was determined to test the hypothesis that high CYP1B1 expression is a risk factor for breast cancer. Large interindividual variations in CYP1B1 expression were found with CYP1B1 levels notably higher in breast cancer patients than cancer-free individuals. The results indicate that CYP1B1 might play a role in breast cancer either through increased PAH activation or through metabolism of endogenous estrogen to a carcinogenic derivative.

Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

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Novakovic Srdjan

2008-09-01

Full Text Available Abstract Background Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations. The current study was aimed at establishing the mutation spectrum of BRCA1/2 in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families. Methods The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the BRCA1/2 screening were: (i probands with at least two first degree relatives with breast and ovarian cancer; (ii probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family. Results Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A BRCA1/2 mutation was found in 56 (39%. Two novel large deletions covering consecutive exons of BRCA1 were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the BRCA1 gene and IVS16-2A>G in the BRCA2 gene. The IVS16-2A>G in the BRCA2 gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the BRCA1/2 positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of

Identification of candidates for postmastectomy radiotherapy in patients with pT3N0M0 breast cancer

International Nuclear Information System (INIS)

Hamamoto, Yasushi; Ohsumi, Shozo; Aogi, Kenjiro; Takashima, Shigemitsu; Shinohara, Shuichi; Nakajima, Naomi; Kataoka, Masaaki

2013-01-01

There is still controversy concerning the indication of postmastectomy radiotherapy (PMRT) for pT3N0M0 breast cancer. To identify the candidates for PMRT in this subset, we investigated failure patterns, and searched for risk factors for isolated locoregional failure in pT3N0M0 breast cancer after mastectomy without PMRT. Among 1,176 patients who received mastectomy without PMRT for untreated unilateral breast cancer between 1990 and 2002, 64 patients (5%) had pT3N0M0 breast cancer (age 30-81 years; median 52.5 years). Isolated locoregional failure as the initial failure occurred in three patients. For all 64 patients, the 8-year failure-free survival rate, the isolated locoregional failure-free rate, and the distant failure-free rate were 76, 93, and 82%, respectively. Incidence of isolated locoregional failure as the initial failure was 18% (2/11) for patients 40 years or younger and 2% (1/53) for patients older than 40 years. The 8-year isolated locoregional failure-free rates were 73% for patients 40 years or younger and 98% for patients older than 40 years (p=0.0135). Concerning pT3N0M0 breast cancer, incidence of isolated locoregional failure was comparatively low after mastectomy without PMRT. Routine use of PMRT for all pT3N0M0 patients seemed to be unacceptable. PMRT may be useful for younger patients because of the comparatively high incidence of isolated locoregional failure. Because of the small number of cases in our series, further studies are necessary to determine the usefulness of PMRT for younger patients with pT3N0M0 breast cancer. (author)

Comprehensive imaging of tumor recurrence in breast cancer patients using whole-body MRI at 1.5 and 3 T compared to FDG-PET-CT

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Schmidt, Gerwin P. [Institute of Clinical Radiology, University Hospitals Munich-Grosshadern, Marchioninistr. 15, 81377 Munich (Germany)], E-mail: gerwin.schmidt@med.uni-muenchen.de; Baur-Melnyk, Andrea [Institute of Clinical Radiology, University Hospitals Munich-Grosshadern, Marchioninistr. 15, 81377 Munich (Germany); Haug, Alexander [Department of Nuclear Medicine, University Hospitals Munich-Grosshadern, 81377 Munich (Germany); Heinemann, Volker [Department of Internal Medicine III, University Hospitals Munich-Grosshadern, 81377 Munich (Germany); Bauerfeind, Ingo [Department of Obstetrics and Gynecology, University Hospitals Munich-Grosshadern, 81377 Munich (Germany); Reiser, Maximilian F. [Institute of Clinical Radiology, University Hospitals Munich-Grosshadern, Marchioninistr. 15, 81377 Munich (Germany); Schoenberg, Stefan O. [Institute of Clinical Radiology University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg (Germany)

2008-01-15

Purpose: To compare the diagnostic accuracy for the detection of tumor recurrence in breast cancer patients using whole-body-MRI (WB-MRI) at 1.5 or 3 T compared to FDG-PET-CT. Materials and methods: Thirty-three female patients with breast cancer and suspicion of recurrence underwent FDG-PET-CT and WB-MRI. Coronal T1w-TSE- and STIR-sequences, HASTE-imaging of the lungs, contrast-enhanced T1w- and T2w-TSE-sequences of the liver, brain and abdomen were performed, using a WB-MRI-scanner at 1.5 (n = 23) or 3 T (n = 10). Presence of local recurrence, lymph node involvement and distant metastatic disease was assessed using clinical and radiological follow-up as a standard of reference. Results: Tumor recurrence was found in 20 of 33 patients. Overall 186 malignant foci were detected with WB-MRI and PET-CT. Both modalities revealed two recurrent tumors of the breast. PET-CT detected more lymph node metastases (n = 21) than WB-MRI (n = 16). WB-MRI was more precise in the detection of distant metastases (n = 154 versus n = 147). Sensitivity was 93% (172/186) and 91% (170/186) for WB-MRI and PET-CT, specificity was 86% (66/77) and 90% (69/77), respectively. Examination times for WB-MRI at 1.5 and 3 T were 51 and 43 min, respectively, examination time for PET-CT was 103 min. Conclusion: WB-MRI and PET-CT are useful for the detection of tumor recurrence in the follow-up of breast cancer. WB-MRI is highly sensitive to distant metastatic disease. PET-CT is more sensitive in detecting lymph node involvement. Tumor screening with WB-MRI is feasible at 1.5 and 3 T, scan time is further reduced at 3 T with identical resolution.

T4 category revision enhances the accuracy and significance of stage III breast cancer.

Science.gov (United States)

Güth, Uwe; Singer, Gad; Langer, Igor; Schötzau, Andreas; Herberich, Linda; Holzgreve, Wolfgang; Wight, Edward

2006-06-15

Because of the considerable heterogeneity in breast carcinoma with noninflammatory skin involvement (T4b/Stage IIIB), a revision was proposed of the TNM staging system that would classify these tumors exclusively based on their tumor size and lymph node status. In the current study, the authors evaluated how implementation of this proposal will affect Stage III noninflammatory breast cancer. Two hundred seven patients who were classified with noninflammatory Stage III breast cancer were treated consecutively between 1990 and 1999 at the University Hospital Basel, Switzerland. To assess the extent of T4b/Stage IIIB tumors independent of the clinicopathologic feature of skin involvement, the reclassification was undertaken. Of 68 patients who had nonmetastatic T4b breast cancer, 37 patients (54.4%) had a tumor extent in accordance with Stage I/II and had improved disease-specific survival (DSS) compared with patients who had Stage III breast cancer (P = .008). Excluding those patients from Stage III led to a 17.9% reduction of the number of patients in this group (n = 170 patients). The 10-year DSS declined from 48.5% to 42.9%. Considerable numbers of patients who are classified with noninflammatory Stage IIIB breast cancer show only a limited disease extent. Through a revision of the T4 category, these low-risk patients were excluded from the highest nonmetastatic TNM stage, and overstaging could be avoided. This procedure decreased the degree of heterogeneity of the entire Stage III group and may result in a more precise assessment of this disease entity. Copyright 2006 American Cancer Society.

Tumor-suppressor activity of RRIG1 in breast cancer

International Nuclear Information System (INIS)

Zhang, Guihong; Brewster, Abenaa; Guan, Baoxiang; Fan, Zhen; Brown, Powel H; Xu, Xiao-Chun

2011-01-01

Retinoid receptor-induced gene-1 (RRIG1) is a novel gene that has been lost in several types of human cancers. The aim of this study was to determine whether RRIG1 plays a role in breast cancer, such as in the suppression of breast cancer cell growth and invasion. Immunohistochemistry was used to detect RRIG1 expression in breast tissue specimens. Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential. Reverse-transcription polymerase chain reaction and western blot assays were used to detect the changes in gene expression. The RhoA activation assay was used to assess RRIG1-induced inhibition of RhoA activity. The immunohistochemical data showed that RRIG1 expression was reduced in breast cancer tissues compared with normal and atypical hyperplastic breast tissues. RRIG1 expression was inversely correlated with lymph node metastasis of breast cancer but was not associated with the status of hormone receptors, such as estrogen receptor, progesterone receptor, or HER2. Furthermore, restoration of RRIG1 expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells. Expression of RRIG1 also reduced phosphorylated Erk1/2 and Akt levels; c-Jun, MMP9, and Akt expressions; and RhoA activity. In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential. The data from the current study indicated that RRIG1 expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity. Future studies will determine the underlying molecular mechanisms and define RRIG1 as a tumor-suppressor gene in breast cancer

Specificity of choline metabolites for in vivo diagnosis of breast cancer using {sup 1}H MRS at 1.5 T

Energy Technology Data Exchange (ETDEWEB)

Stanwell, Peter; Gluch, Laurence; Lean, Cynthia; Malycha, Peter; Mountford, Carolyn [Royal North Shore Hospital, Institute for Magnetic Resonance Research and Department of Magnetic Resonance in Medicine, University of Sydney, St Leonards, NSW (Australia); Clark, David [Breast Centre, Waratah, NSW (Australia); Tomanek, Boguslaw [National Research Council Canada, Institute for Biodiagnostics, Winnipeg, MB (Canada); Baker, Luke [Sydney Adventist Hospital, Department of Radiology, Wahroonga, NSW (Australia); Giuffre, Bruno [Royal North Shore Hospital, Department of Radiology, St Leonards, NSW (Australia)

2005-05-01

The purpose was to determine if in vivo proton magnetic resonance spectroscopy ({sup 1}H MRS) at 1.5 T can accurately provide the correct pathology of breast disease. Forty-three asymptomatic volunteers including three lactating mothers were examined and compared with 21 breast cancer patients. Examinations were undertaken at 1.5 T using a purpose-built transmit-receive single breast coil. Single voxel spectroscopy was undertaken using echo times of 135 and 350 ms. The broad composite resonance at 3.2 ppm, which includes contributions from choline, phosphocholine (PC), glycerophosphocholine (GPC), myo-inositol and taurine, was found not to be a unique marker for malignancy providing a diagnostic sensitivity and specificity of 80.0 and 86.0%, respectively. This was due to three of the asymptomatic volunteers and all of the lactating mothers also generating the broad composite resonance at 3.2 ppm. Optimised post-acquisitional processing of the spectra resolved a resonance at 3.22 ppm, consistent with PC, in patients with cancer. In contrast the spectra recorded for three false-positive volunteers, and the three lactating mothers had a resonance centred at 3.28 ppm (possibly taurine, myo-inositol or GPC). This improved the specificity of the test to 100%. Careful referencing of the spectra and post-acquisitional processing intended to optimise spectral resolution of in vivo MR proton spectra from human breast tissue resolves the composite choline resonance. This allows the distinction of patients with malignant disease from volunteers with a sensitivity of 80% and specificity of 100%. Therefore, resolution of the composite choline resonance into its constituent components improves the specificity of the in vivo {sup 1}H MRS method, but does not overcome the problem of 20% false-negatives. (orig.)

[Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer?].

Science.gov (United States)

Sénéchal, Claire; Reyal, Fabien; Callet, Nasrine; This, Pascale; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Fourme, Emmanuelle

2016-03-01

In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

FLI1 Expression in Breast Cancer Cell Lines and Primary Breast Carcinomas is Correlated with ER, PR and HER2

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Inam Jasim Lafta

2017-12-01

Full Text Available FLI1 is a member of ETS family of transcription factors that regulate a variety of normal biologic activities including cell proliferation, differentiation, and apoptosis. The expression of FLI1 and its correlation with well-known breast cancer prognostic markers (ER, PR and HER2 was determined in primary breast tumors as well as four breast cancer lines including: MCF-7, T47D, MDA-MB-231 and MDA-MB-468 using RT-qPCR with either 18S rRNA or ACTB (β-actin for normalization of data. FLI1 mRNA level was decreased in the breast cancer cell lines under study compared to the normal breast tissue; however, Jurkat cells, which were used as a positive control, showed overexpression compared to the normal breast. Regarding primary breast carcinomas, FLI1 is significantly under expressed in all of the stages of breast cancer upon using 18S as an internal control. This FLI1 expression was correlated with ER, PR and HER2 status. In conclusion FLI1 can be exploited as a preliminary marker that can predict the status of ER, PR and HER2 in primary breast tumors.

Genetic Polymorphisms in the EGFR (R521K and Estrogen Receptor (T594T Genes, EGFR and ErbB-2 Protein Expression, and Breast Cancer Risk in Tunisia

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Imen Kallel

2009-01-01

Full Text Available We evaluated the association of epidermal growth factor receptor (EGFR 142285G>A (R521K and estrogen receptor alpha (ESR1 2014G>A (T594T single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg genotype was more prevalent in patients with lymph node metastasis (=.03 and high grade tumors (=.011. The ESR1 2014G allele showed significant association with breast cancer risk (=.025. The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (=.009; =.021, resp.. These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.

Genetic variation in CYP19A1 and risk of breast cancer and fibrocystic breast conditions among women in Shanghai, China.

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Chen, Chu; Sakoda, Lori C; Doherty, Jennifer A; Loomis, Melissa M; Fish, Sherianne; Ray, Roberta M; Lin, Ming Gang; Fan, Wenhong; Zhao, Lue Ping; Gao, Dao Li; Stalsberg, Helge; Feng, Ziding; Thomas, David B

2008-12-01

CYP19A1 encodes for aromatase, which irreversibly converts androgens to estrogens; variation in this gene may affect individual susceptibility to breast cancer and other sex hormone-dependent outcomes. In a case-control study nested within a breast self-examination trial conducted in China, we examined whether CYP19A1 polymorphisms (rs1870049, rs1004982, rs28566535, rs936306, rs11636639, rs767199, rs4775936, rs11575899, rs10046, and rs4646) were associated with risk of breast cancer and fibrocystic breast conditions. Cases were diagnosed with breast cancer (n = 614) or fibrocystic breast conditions (n = 465) during 1989 to 2000. Controls were free of breast disease during the same period (n = 879). Presence of proliferative changes within the extratumoral tissue of women with breast cancer and the lesions of women with fibrocystic conditions only was assessed. None of the polymorphisms were associated with overall risk of breast cancer or fibrocystic breast conditions. Differences in breast cancer risk, however, were observed by proliferation status. The risk of breast cancer with (but not without) proliferative fibrocystic conditions was increased among women homozygous for the minor allele of rs1004982 (C), rs28566535 (C), rs936306 (T), and rs4775936 (C) relative to those homozygous for the major allele [age-adjusted odds ratios (95% confidence intervals), 2.19 (1.24-3.85), 2.20 (1.27-3.82), 1.94 (1.13-3.30), and 1.95 (1.07-3.58), respectively]. Also, haplotypes inferred using all polymorphisms were not associated with overall risk of either outcome, although some block-specific haplotypes were associated with an increased risk of breast cancer with concurrent proliferative fibrocystic conditions. Our findings suggest that CYP19A1 variation may enhance breast cancer development in some women, but further confirmation is warranted.

Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers

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Finkelman, Brian S.; Rubinstein, Wendy S.; Friedman, Sue; Friebel, Tara M.; Dubitsky, Shera; Schonberger, Niecee Singer; Shoretz, Rochelle; Singer, Christian F.; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie; Garber, Judy E.; Schildkraut, Joellen; Daly, Mary B.; Isaacs, Claudine; Pichert, Gabrielle; Neuhausen, Susan L.; Couch, Fergus J.; van't Veer, Laura; Eeles, Rosalind; Bancroft, Elizabeth; Evans, D. Gareth; Ganz, Patricia A.; Tomlinson, Gail E.; Narod, Steven A.; Matloff, Ellen; Domchek, Susan; Rebbeck, Timothy R.

2012-01-01

Purpose Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. Methods Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. Results Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. Conclusion Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care. PMID:22430266

Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity

DEFF Research Database (Denmark)

Tchatchou, Sandrine; Riedel, Angela; Lyer, Stefan

2010-01-01

,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region......According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer...... and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C...

Diffusion-weighted magnetic resonance imaging combined with T2-weighted images in the detection of small breast cancer: a single-center multi-observer study.

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Wu, Lian-Ming; Chen, Jie; Hu, Jiani; Gu, Hai-Yan; Xu, Jian-Rong; Hua, Jia

2014-02-01

Breast cancer is the most common cancer in women worldwide. However, it remains a difficult diagnosis problem to differentiate between benign and malignant breast lesions, especially in small early breast lesions. To assess the diagnostic value of diffusion-weighted imaging (DWI) combined with T2-weighted imaging (T2WI) for small breast cancer characterization. Fifty-eight patients (65 lesions) with a lesion breast magnetic resonance imaging (MRI) including DWI and histological analysis. Three observers with varying experience levels reviewed MRI. The probability of breast cancer in each lesion on MR images was recorded with a 5-point scale. Areas under the receiver-operating characteristic curve (AUCs) were compared by using the Z test; sensitivity and specificity were determined with the Z test after adjusting for data clustering. AUC of T2WI and DWI (Observer 1, 0.95; Observer 2, 0.91; Observer 3, 0.83) was greater than that of T2WI (Observer 1, 0.80; Observer 2, 0.74; Observer 3, 0.70) for all observers (P breast cancer characterization. It should be considered selectively in the preoperative evaluation of patients with small lesions of the breast.

MicroRNA-223 Targeting STIM1 Inhibits the Biological Behavior of Breast Cancer

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Yanfang Yang

2018-01-01

Full Text Available Background/Aims: To investigate the cellular effects and clinical significance of microRNA-223 (miR-223 in breast cancer by targeting stromal interaction molecule1 (STIM1. Methods: Breast cancer cell lines (T47D, MCF-7, SKB-R3, MDA-MB-231 and MDA-MB-435 and a normal breast epithelial cell line (MCF-10A were prepared for this study. MiR-223 mimics, anti-miR-223 and pcDNA 3.1-STIM1 were transiently transfected into cancer cells independently or together, and then RT-qPCR was performed to detect the expressions of miR-223 and STIM1 mRNA, dual-luciferase reporter assay was conducted to examine the effects of miR-223 on STIM1, Western blotting was used to measure the expressions of the STIM1 proteins, MTT and Trans-well assays were performed to detect cell proliferation and invasion. Finally, the correlation of miR-223 and STIM1 was investigated by detecting with ISH and IHC in breast cancer specimens or the corresponding adjacent normal tissues. Results: Compared with normal cells and tissues, breast cancer tissues and cells exhibited significantly lower expression of miR-223, but higher expression of STIM1. MiR-223 could inhibit the proliferation and invasiveness of breast cancer cells by negatively regulating the expressions of STIM1. Reimplantation with STIM1 partially rescued the miRNA-223-induced inhibition of breast cancer cells. Clinical data revealed that high expression of STIM1 and miR-223 was respectively detrimental and beneficial factor impacting patient’s disease-free survival (DFS rather than overall survival (OS. Moreover, Pearson correlation analysis also confirmed that STIM1 was inversely correlated with miR-223. Conclusion: MiR-223 inhibits the proliferation and invasion of breast cancer by targeting STIM1. The miR-223/STIM1 axis could possibly be a potential therapeutic target for treating breast cancer patients.

The hOGG1 Ser326Cys Gene Polymorphism and Breast Cancer Risk in Saudi Population.

Science.gov (United States)

Alanazi, Mohammed; Pathan, Akbar Ali Khan; Shaik, Jilani P; Alhadheq, Abdullah; Khan, Zahid; Khan, Wajahatullah; Al Naeem, Abdulrahman; Parine, Narasimha Reddy

2017-07-01

The purpose of this study was to test the association between human 8-oxoguanine glycosylase 1 (hOGG1) gene polymorphisms and susceptibility to breast cancer in Saudi population. We have also aimed to screen the hOGG1 Ser326Cys polymorphism effect on structural and functional properties of the hOGG1 protein using in silico tools. We have analyzed four SNPs of hOGG1 gene among Saudi breast cancer patients along with healthy controls. Genotypes were screened using TaqMan SNP genotype analysis method. Experimental data was analyzed using Chi-square, t test and logistic regression analysis using SPSS software (v.16). In silco analysis was conducted using discovery studio and HOPE program. Genotypic analysis showed that hOGG1 rs1052133 (Ser326Cys) is significantly associated with breast cancer samples in Saudi population, however rs293795 (T >C), rs2072668 (C>G) and rs2075747 (G >A) did not show any association with breast cancer. The hOGG1 SNP rs1052133 (Ser326Cys) minor allele T showed a significant association with breast cancer samples (OR = 1.78, χ2 = 7.86, p = 0.02024). In silico structural analysis was carried out to compare the wild type (Ser326) and mutant (Cys326) protein structures. The structural prediction studies revealed that Ser326Cys variant may destabilize the protein structure and it may disturb the hOGG1 function. Taken together this is the first In silico study report to confirm Ser326Cys variant effect on structural and functional properties of hOGG1 gene and Ser326Cys role in breast cancer susceptibility in Saudi population.

Association of Cytochrome CYP1A1 Gene Polymorphisms and Tobacco Smoking With the Risk of Breast Cancer in Women From Iraq

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Hassan M. Naif

2018-04-01

Full Text Available BackgroundCYP1A1 gene polymorphisms and tobacco smoking are among several risk factors for various types of cancers, but their influence on breast cancer remains controversial. We analyzed the possible association of CYP1A1 gene polymorphisms and tobacco smoking-related breast cancer in women from Iraq.Materials and methodsIn this case–control study, gene polymorphism of CYP1A1 gene (CYP1A1m1, T6235C and CYP1A1m2, A4889G of 199 histologically verified breast cancer patients’ and 160 cancer-free control women’s specimens were performed by using PCR-based restriction fragment length polymorphism.ResultsThree genotype frequencies (TT, TC, and CC of CYP1A1m1T/C appeared in 16.1, 29.6, and 54.3% of women with breast cancer, respectively, compared with 41.2, 40, and 18.8% in the control group, respectively. CYP1A1m1 CC genotype and C allele were significantly associated with increased risks for breast cancer in patients (54.3 and 69%, respectively compared with controls (18.8 and 39%, respectively. While the three genotype frequencies (AA, AG, and GG of CYP1A1m2A/G were detected in 20.1, 31.2, and 48.7% in patients compared with 46.3, 40.6, and 13.1% in controls, respectively. The frequency of GG genotypes and G allele was significantly higher in patients (48.7 and 64%, respectively than in the controls (13.1 and 33%, respectively. Smoking women having either CC or GG genotypes showed a highly significant association with increased risk of breast cancer [odds ratio (OR = 1.607, 95% confidence interval (CI 0.91–1.64, p = 0.0001, and OR, 1.841, 95% CI, 0.88–1.67, p = 0.0001, respectively]. On the other hand, the T and A alleles of predominantly seen in healthy smoking women (83 and 85%, p = 0.0001, respectively.ConclusionThese findings indicated that both C and G alleles of CYP1A1m1 and m2 were significantly associated with elevated risk of breast cancer in Iraqi women, while the T and A alleles were predominantly seen in

BACH1 Ser919Pro variant and breast cancer risk

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Eerola Hannaleena

2006-01-01

Full Text Available Abstract Background BACH1 (BRCA1-associated C-terminal helicase 1; also known as BRCA1-interacting protein 1, BRIP1 is a helicase protein that interacts in vivo with BRCA1, the protein product of one of the major genes for hereditary predisposition to breast cancer. Previously, two BACH1 germ line missense mutations have been identified in early-onset breast cancer patients with and without family history of breast and ovarian cancer. In this study, we aimed to evaluate whether there are BACH1 genetic variants that contribute to breast cancer risk in Finland. Methods The BACH1 gene was screened for germ line alterations among probands from 43 Finnish BRCA1/2 negative breast cancer families. Recently, one of the observed common variants, Ser-allele of the Ser919Pro polymorphism, was suggested to associate with an increased breast cancer risk, and was here evaluated in an independent, large series of 888 unselected breast cancer patients and in 736 healthy controls. Results Six BACH1 germ line alterations were observed in the mutation analysis, but none of these were found to associate with the cancer phenotype. The Val193Ile variant that was seen in only one family was further screened in an independent series of 346 familial breast cancer cases and 183 healthy controls, but no additional carriers were observed. Individuals with the BACH1 Ser919-allele were not found to have an increased breast cancer risk when the Pro/Ser heterozygotes (OR 0.90; 95% CI 0.70–1.16; p = 0.427 or Ser/Ser homozygotes (OR 1.02; 95% CI 0.76–1.35; p = 0.91 were compared to Pro/Pro homozygotes, and there was no association of the variant with any breast tumor characteristics, age at cancer diagnosis, family history of cancer, or survival. Conclusion Our results suggest that the BACH1 Ser919 is not a breast cancer predisposition allele in the Finnish study population. Together with previous studies, our results also indicate that although some rare germ line variants

BACH1 Ser919Pro variant and breast cancer risk

International Nuclear Information System (INIS)

Vahteristo, Pia; Yliannala, Kristiina; Tamminen, Anitta; Eerola, Hannaleena; Blomqvist, Carl; Nevanlinna, Heli

2006-01-01

BACH1 (BRCA1-associated C-terminal helicase 1; also known as BRCA1-interacting protein 1, BRIP1) is a helicase protein that interacts in vivo with BRCA1, the protein product of one of the major genes for hereditary predisposition to breast cancer. Previously, two BACH1 germ line missense mutations have been identified in early-onset breast cancer patients with and without family history of breast and ovarian cancer. In this study, we aimed to evaluate whether there are BACH1 genetic variants that contribute to breast cancer risk in Finland. The BACH1 gene was screened for germ line alterations among probands from 43 Finnish BRCA1/2 negative breast cancer families. Recently, one of the observed common variants, Ser-allele of the Ser919Pro polymorphism, was suggested to associate with an increased breast cancer risk, and was here evaluated in an independent, large series of 888 unselected breast cancer patients and in 736 healthy controls. Six BACH1 germ line alterations were observed in the mutation analysis, but none of these were found to associate with the cancer phenotype. The Val193Ile variant that was seen in only one family was further screened in an independent series of 346 familial breast cancer cases and 183 healthy controls, but no additional carriers were observed. Individuals with the BACH1 Ser919-allele were not found to have an increased breast cancer risk when the Pro/Ser heterozygotes (OR 0.90; 95% CI 0.70–1.16; p = 0.427) or Ser/Ser homozygotes (OR 1.02; 95% CI 0.76–1.35; p = 0.91) were compared to Pro/Pro homozygotes, and there was no association of the variant with any breast tumor characteristics, age at cancer diagnosis, family history of cancer, or survival. Our results suggest that the BACH1 Ser919 is not a breast cancer predisposition allele in the Finnish study population. Together with previous studies, our results also indicate that although some rare germ line variants in BACH1 may contribute to breast cancer development, the

Association of ESR1 gene tagging SNPs with breast cancer risk

Science.gov (United States)

Dunning, Alison M.; Healey, Catherine S.; Baynes, Caroline; Maia, Ana-Teresa; Scollen, Serena; Vega, Ana; Rodríguez, Raquel; Barbosa-Morais, Nuno L.; Ponder, Bruce A.J.; Low, Yen-Ling; Bingham, Sheila; Haiman, Christopher A.; Le Marchand, Loic; Broeks, Annegien; Schmidt, Marjanka K.; Hopper, John; Southey, Melissa; Beckmann, Matthias W.; Fasching, Peter A.; Peto, Julian; Johnson, Nichola; Bojesen, Stig E.; Nordestgaard, Børge; Milne, Roger L.; Benitez, Javier; Hamann, Ute; Ko, Yon; Schmutzler, Rita K.; Burwinkel, Barbara; Schürmann, Peter; Dörk, Thilo; Heikkinen, Tuomas; Nevanlinna, Heli; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chen, Xiaoqing; Spurdle, Amanda; Change-Claude, Jenny; Flesch-Janys, Dieter; Couch, Fergus J.; Olson, Janet E.; Severi, Gianluca; Baglietto, Laura; Børresen-Dale, Anne-Lise; Kristensen, Vessela; Hunter, David J.; Hankinson, Susan E.; Devilee, Peter; Vreeswijk, Maaike; Lissowska, Jolanta; Brinton, Louise; Liu, Jianjun; Hall, Per; Kang, Daehee; Yoo, Keun-Young; Shen, Chen-Yang; Yu, Jyh-Cherng; Anton-Culver, Hoda; Ziogoas, Argyrios; Sigurdson, Alice; Struewing, Jeff; Easton, Douglas F.; Garcia-Closas, Montserrat; Humphreys, Manjeet K.; Morrison, Jonathan; Pharoah, Paul D.P.; Pooley, Karen A.; Chenevix-Trench, Georgia

2009-01-01

We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55 000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02–1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms. PMID:19126777

Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers

Science.gov (United States)

Park, Daniel J.; Tao, Kayoko; Le Calvez-Kelm, Florence; Nguyen-Dumont, Tu; Robinot, Nivonirina; Hammet, Fleur; Odefrey, Fabrice; Tsimiklis, Helen; Teo, Zhi L.; Thingholm, Louise B.; Young, Erin L.; Voegele, Catherine; Lonie, Andrew; Pope, Bernard J.; Roane, Terrell C.; Bell, Russell; Hu, Hao; Shankaracharya; Huff, Chad D.; Ellis, Jonathan; Li, Jun; Makunin, Igor V.; John, Esther M.; Andrulis, Irene L.; Terry, Mary B.; Daly, Mary; Buys, Saundra S.; Snyder, Carrie; Lynch, Henry T.; Devilee, Peter; Giles, Graham G.; Hopper, John L.; Feng, Bing J.; Lesueur, Fabienne; Tavtigian, Sean V.; Southey, Melissa C.; Goldgar, David E.

2014-01-01

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del) and c.1207G>T (p.D403Y). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003). PMID:25050558

Significance of Additional Non-Mass Enhancement in Patients with Breast Cancer on Preoperative 3T Dynamic Contrast Enhanced MRI of the Breast

International Nuclear Information System (INIS)

Cho, Yun Hee; Cho, Kyu Ran; Park, Eun Kyung; Seo, Bo Kyoung; Woo, Ok Hee; Cho, Sung Bum; Bae, Jeoung Won

2016-01-01

In preoperative assessment of breast cancer, MRI has been shown to identify more additional breast lesions than are detectable using conventional imaging techniques. The characterization of additional lesions is more important than detection for optimal surgical treatment. Additional breast lesions can be included in focus, mass, and non-mass enhancement (NME) on MRI. According to the fifth edition of the breast imaging reporting and data system (BI-RADS®), which includes several changes in the NME descriptors, few studies to date have evaluated NME in preoperative assessment of breast cancer. We investigated the diagnostic accuracy of BI-RADS descriptors in predicting malignancy for additional NME lesions detected on preoperative 3T dynamic contrast enhanced MRI (DCE-MRI) in patients with newly diagnosed breast cancer. Between January 2008 and December 2012, 88 patients were enrolled in our study, all with NME lesions other than the index cancer on preoperative 3T DCE-MRI and all with accompanying histopathologic examination. The MRI findings were analyzed according to the BI-RADS MRI lexicon. We evaluated the size, distribution, internal enhancement pattern, and location of NME lesions relative to the index cancer (i.e., same quadrant, different quadrant, or contralateral breast). On histopathologic analysis of the 88 NME lesions, 73 (83%) were malignant and 15 (17%) were benign. Lesion size did not differ significantly between malignant and benign lesions (P = 0.410). Malignancy was more frequent in linear (P = 0.005) and segmental (P = 0.011) distributions, and benignancy was more frequent in focal (P = 0.004) and regional (P < 0.001) NME lesions. The highest positive predictive value (PPV) for malignancy occurred in segmental (96.8%), linear (95.1%), clustered ring (100%), and clumped (92.0%) enhancement. Asymmetry demonstrated a high positive predictive value of 85.9%. The frequency of malignancy was higher for NME lesions located in the same quadrant with

Kiss-1/GPR54 protein expression in breast cancer.

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Papaoiconomou, Eleni; Lymperi, Maria; Petraki, Constantina; Philippou, Anastassios; Msaouel, Pavlos; Michalopoulou, Fani; Kafiri, Georgia; Vassilakos, George; Zografos, Georgios; Koutsilieris, Michael

2014-03-01

Numerous studies have shown that the Kiss-1 gene countervails the metastatic aptitude of several cancer cell lines and solid-tumor neoplasias. However, there still remains ambiguity regarding its role in breast cancer and literature has arisen asserting that Kiss-1 expression may be linked to an aggressive phenotype and malignant progression. Herein, we investigated the protein expression of Kiss-1 and its receptor GPR54 in breast cancer tissues compared to non-cancerous mammary tissues. Paraffin-fixed cancer tissues from 43 women with resected breast adenocarcinomas and 11 specimens derived from women suffering from fibrocystic disease, serving as controls, were immunostained with Kiss-1 and GPR54 antibodies. Kiss-1 and GPR54 protein expression levels were significantly higher in breast cancer compared to fibrocystic tissues (pbreast cancer and fibrocystic disease specimens. Kiss-1/GPR54 expression was found to be significantly higher in breast cancer compared to non-malignant mammary tissues.

SATB1 tethers multiple gene loci to reprogram expression profiledriving breast cancer metastasis

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Han, Hye-Jung; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

2006-07-13

Global changes in gene expression occur during tumor progression, as indicated by expression profiling of metastatic tumors. How this occurs is poorly understood. SATB1 functions as a genome organizer by folding chromatin via tethering multiple genomic loci and recruiting chromatin remodeling enzymes to regulate chromatin structure and expression of a large number of genes. Here we show that SATB1 is expressed at high levels in aggressive breast cancer cells, and is undetectable in non-malignant breast epithelial cells. Importantly, RNAi-mediated removal of SATB1 from highly-aggressive MDA-MB-231 cells altered the expression levels of over 1200 genes, restored breast-like acinar polarity in three-dimensional cultures, and prevented the metastastic phenotype in vivo. Conversely, overexpression of SATB1 in the less-aggressive breast cancer cell line Hs578T altered the gene expression profile and increased metastasis dramatically in vivo. Thus, SATB1 is a global regulator of gene expression in breast cancer cells, directly regulating crucial metastasis-associated genes, including ERRB2 (HER2/NEU), TGF-{beta}1, matrix metalloproteinase 3, and metastasin. The identification of SATB1 as a protein that re-programs chromatin organization and transcription profiles to promote breast cancer metastasis suggests a new model for metastasis and may provide means of therapeutic intervention.

Clinical significance of the lymph node ratio in N1 breast cancer

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Kim, Jae Ho; Kim Jin Hee; Kim, Ok Bae; Oh, Young Kee [Dept. of Radiation Oncology, Keimyung University School of Medicine, Daegu (Korea, Republic of); Park, Seung Gyu [Dept. of Radiation Oncology, Dogae Health Subcenter, Gumi (Korea, Republic of)

2017-09-15

The purpose of this study was to evaluate the prognostic value of the lymph node ratio (LNR), which was defined as the proportion of involved nodes of all dissected nodes, in pN1 breast cancer. We retrospectively analyzed the clinical data of patients with pN1 breast cancer (N = 144) treated at Keimyung University Dongsan Medical Center, Daegu, Korea between 2001 and 2010. The median age was 46 years (range, 27 to 66 years). The LNR was 0.01–0.15 (low LNR) in 130 patients and >0.15 (high LNR) in 14 patients. Sixty-five patients (45.1%) had T1 tumors, 74 (51.4%) had T2 tumors, and 5 (3.5%) had T3 tumors. Eighty-eight patients (61.1%) underwent total mastectomy and 56 (38.9%) underwent partial mastectomy. Fifty-nine patients (41.0%) underwent radiotherapy and 12 (8.3%) underwent regional radiotherapy. The median follow-up period was 65 months. The 5- and 10-year disease-free survival (DFS) rates were 92.7% and 82.4%, respectively. Univariate analyses revealed that high LNR (p = 0.004), total mastectomy (p = 0.006), no local radiotherapy (p = 0.036), and stage T2 or T3 (p = 0.010) were associated with worse DFS. In multivariable analysis, only high LNR (p = 0.015) was associated with worse DFS. High LNR is an independent prognostic factor in pN1 breast cancer and could be an indication for adjuvant radiotherapy in these patients.

Association of MTHFR gene polymorphisms with breast cancer survival

International Nuclear Information System (INIS)

Martin, Damali N; Boersma, Brenda J; Howe, Tiffany M; Goodman, Julie E; Mechanic, Leah E; Chanock, Stephen J; Ambs, Stefan

2006-01-01

Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival. We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05–4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31–1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17–6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12–1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, p interaction = 0.088; C677T, p interaction = 0.026). We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival

Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

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Bernal-Estévez, David; Sánchez, Ramiro; Tejada, Rafael E.; Parra-López, Carlos

2016-01-01

Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells. T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy. We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy. Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in

Tissue inhibitor of metalloproteinases-1 in breast cancer

DEFF Research Database (Denmark)

Würtz, Sidse Ørnbjerg; Rasmussen, Anne-Sofie Schrohl; Sørensen, Nanna Møller

2005-01-01

Whether patients diagnosed with primary breast cancer are offered adjuvant systemic therapy following surgical removal of the tumor is based on prognosis. Prognosis is estimated in every patient using established prognostic variables. Unfortunately, when using the currently available prognostic...... parameters a significant proportion of patients are over-treated. Thus, in order to improve stratification of breast cancer patients, additional prognostic factors need to be identified. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of the promising candidates for new prognostic markers in breast...... cancer, as a number of studies have demonstrated an association between high tumor-tissue levels of TIMP-1 mRNA as well as TIMP-1 protein and a poor prognosis of breast cancer patients. TIMP-1 is a member of the TIMP family, currently comprising four members (TIMP-1-4), and its main function...

TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses' Health Study

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Cox, David G; Penney, Kathryn; Guo, Qun; Hankinson, Susan E; Hunter, David J

2007-01-01

Transforming growth factor beta 1 (TGFB1) forms a signaling complex with transforming growth factor beta receptors 1 and 2 and has been described as both a tumor suppressor and tumor promoter. Single nucleotide polymorphisms in TGFB1 and a microsatellite in TGFBR1 have been investigated for association with risk of breast cancer, with conflicting results. We examined polymorphisms in the promoter region of the TGFB1 gene as well as the TGFBR1*6A microsatellite in the Nurses' Health Study cohort. No overall associations between the L10P polymorphism of TGFB1 or the TGFBR1 microsatellite were detected. However, we observed an inverse association between the -509 C/T polymorphism of TGFB1 (p-trend = 0.04), which was stronger and more significant among women with estrogen receptor positive breast cancer. Polymorphisms in the promoter region of TGFB1 are not likely to be associated with large increases in breast cancer risk overall among Caucasian women

Pre-treatment functional MRI of breast cancer: T2* evaluation at 3 T and relationship to dynamic contrast-enhanced and diffusion-weighted imaging.

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Kousi, Evanthia; O'Flynn, Elizabeth A M; Borri, Marco; Morgan, Veronica A; deSouza, Nandita M; Schmidt, Maria A

2018-05-31

Baseline T2* relaxation time has been proposed as an imaging biomarker in cancer, in addition to Dynamic Contrast-Enhanced (DCE) MRI and diffusion-weighted imaging (DWI) parameters. The purpose of the current work is to investigate sources of error in T2* measurements and the relationship between T2* and DCE and DWI functional parameters in breast cancer. Five female volunteers and thirty-two women with biopsy proven breast cancer were scanned at 3 T, with Research Ethics Committee approval. T2* values of the normal breast were acquired from high-resolution, low-resolution and fat-suppressed gradient-echo sequences in volunteers, and compared. In breast cancer patients, pre-treatment T2*, DCE MRI and DWI were performed at baseline. Pathologically complete responders at surgery and non-responders were identified and compared. Principal component analysis (PCA) and cluster analysis (CA) were performed. There were no significant differences between T2* values from high-resolution, low-resolution and fat-suppressed datasets (p > 0.05). There were not significant differences between baseline functional parameters in responders and non-responders (p > 0.05). However, there were differences in the relationship between T2* and contrast-agent uptake in responders and non-responders. Voxels of similar characteristics were grouped in 5 clusters, and large intra-tumoural variations of all parameters were demonstrated. Breast T2* measurements at 3 T are robust, but spatial resolution should be carefully considered. T2* of breast tumours at baseline is unrelated to DCE and DWI parameters and contribute towards describing functional heterogeneity of breast tumours. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

The UGT1A6_19_GG genotype is a breast cancer risk factor

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Christina eJustenhoven

2013-06-01

Full Text Available Validation of an association between the UGT1A6_19_T>G (rs6759892 polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA. An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS, Germany (BBCC and Sweden (SASBAC. The pooled analysis included 7,418 cases and 8,720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05-1.22; p = 0.001. The pooled study showed a similar effect (OR 1.09, 95% CI 1.04-1.14; p = 0.001. We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.

High resolution MRI of the breast at 3 T: which BI-RADS registered descriptors are most strongly associated with the diagnosis of breast cancer?

International Nuclear Information System (INIS)

Pinker-Domenig, K.; Helbich, T.H.; Bogner, W.; Gruber, S.; Bickel, H.; Duffy, S.; Schernthaner, M.; Dubsky, P.; Pluschnig, U.; Rudas, M.; Trattnig, S.

2012-01-01

To identify which breast lesion descriptors in the ACR BI-RADS registered MRI lexicon are most strongly associated with the diagnosis of breast cancer when performing breast MR imaging at 3 T. 150 patients underwent breast MR imaging at 3 T. Lesion size, morphology and enhancement kinetics were assessed according to the BI-RADS registered classification. Sensitivity, specificity and diagnostic accuracy were assessed. The effects of the BI-RADS registered descriptors on sensitivity and specificity were evaluated. Data were analysed using logistic regression. Histopathological diagnoses were used as the standard of reference. The sensitivity, specificity and diagnostic accuracy of breast MRI at 3 T was 99%, 81% and 93%, respectively. In univariate analysis, the final diagnosis of malignancy was positively associated with irregular shape (p registered breast lesion descriptors that are mostly strongly associated with breast cancer in breast MR imaging at 3 T are lesion shape, lesion margin, internal enhancement pattern and Type 3 enhancement kinetics. (orig.)

CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

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Minlan Yang

2017-11-01

Full Text Available Abstract Background Claudin-6 (CLDN6, a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. Methods We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM, 5-fluorouracil (5-FU, and cisplatin (DDP was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1 was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. Results Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi –mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to

RAD51B in Familial Breast Cancer

DEFF Research Database (Denmark)

Pelttari, Liisa M; Khan, Sofia; Vuorela, Mikko

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition......, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD......51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients...

In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice

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Abu N

2015-03-01

Full Text Available Nadiah Abu,1,2 Nurul Elyani Mohamed,2 Swee Keong Yeap,3 Kian Lam Lim,4 M Nadeem Akhtar,5 Aimi Jamil Zulfadli,3 Beh Boon Kee,2 Mohd Puad Abdullah,2 Abdul Rahman Omar,3 Noorjahan Banu Alitheen2 1Bright Sparks Unit, Universiti Malaya, Kuala Lumpur, Malaysia; 2Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, 3Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia; 4Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Lot PT, Jalan Sungai Long, Bandar Sungai Long, Cheras, Selangor, Malaysia; 5Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Kuantan Pahang, Malaysia Abstract: Flavokawain B (FKB is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum. It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit

Glioma-Associated Oncogene Homolog Inhibitors Have the Potential of Suppressing Cancer Stem Cells of Breast Cancer.

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Jeng, Kuo-Shyang; Jeng, Chi-Juei; Sheen, I-Shyan; Wu, Szu-Hua; Lu, Ssu-Jung; Wang, Chih-Hsuan; Chang, Chiung-Fang

2018-05-05

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.

ATM variants and cancer risk in breast cancer patients from Southern Finland

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Aittomäki Kristiina

2006-08-01

Full Text Available Abstract Background Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. Methods Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. Results Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. Conclusion Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with

Glutathione S-transferase M1 and P1 polymorphisms and risk of breast cancer and fibrocystic breast conditions in Chinese women.

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Sakoda, Lori C; Blackston, Christie R; Xue, Kan; Doherty, Jennifer A; Ray, Roberta M; Lin, Ming Gang; Stalsberg, Helge; Gao, Dao Li; Feng, Ziding; Thomas, David B; Chen, Chu

2008-05-01

Enzymes encoded by the glutathione S-tranferase mu 1 (GSTM1) and pi 1 (GSTP1) genes, which are expressed in breast tissue, catalyze the detoxification of endogenous and exogenous electrophiles. Reduced enzyme activity, due to carriage of the GSTM1 deletion or the GSTP1 Ile105Val Val allele, may therefore affect susceptibility to breast cancer and related conditions. In a case-control study of Chinese women, we examined whether these polymorphisms were associated with risk of breast cancer and fibrocystic breast conditions. Women diagnosed with breast cancer (n=615) or fibrocystic breast conditions (n=467) were compared to women without clinical breast disease (n=878). We also examined whether these associations differed by menopausal status or by presence of proliferation in the extra-tumoral epithelium among women with breast cancer and in lesions among women with fibrocystic conditions. No overall association of either GST polymorphism with risk of breast cancer or fibrocystic breast conditions was observed. There was some evidence of slightly elevated cancer risk associated with carriage of the GSTM1 null genotype and at least one GSTP1 105-Val allele (OR=1.33, 95% CI, 0.99-1.80), compared to carriage of the GSTM1 non-null and GSTP1 Ile/Ile genotypes. This relationship was stronger in women who had breast cancer with extra-tumoral tissue proliferation (OR=1.77, 95% CI, 1.03-3.04). Our results suggest that GSTM1 and GSTP1 genotypes do not individually influence susceptibility to breast cancer or fibrocystic breast conditions. The observed increased risk of breast cancer associated with joint carriage of the GSTM1 null genotype and GSTP1 105-Val allele needs confirmation in other studies.

beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

International Nuclear Information System (INIS)

Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

2008-01-01

β1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of β1 integrin signaling. We showed previously that β1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and β1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo

beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

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Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

2008-06-02

{beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

Mutation analysis of breast cancer gene BRCA among breast cancer Jordanian females

International Nuclear Information System (INIS)

Atoum, Manar F.; Al-Kayed, Sameer A.

2004-01-01

To screen mutations of the tumor suppressor breast cancer susceptibility gene 1 (BRCA1) within 3 exons among Jordanian breast cancer females. A total of 135 Jordanian breast cancer females were genetically analyzed by denaturing gradient electrophoresis (DGGE) for mutation detection in 3 BRCA1 exons (2, 11 and 20) between 2000-2002 in Al-Basheer Hospital, Amman, Jordan. Of the studied patients 50 had a family history of breast cancer, 28 had a family history of cancer other than breast cancer, and 57 had no family history of any cancer. Five germline mutations were detected among breast cancer females with a family history of breast cancers (one in exon 2 and 4 mutations in exon 11). Another germline mutation (within exon 11) was detected among breast cancer females with family history of cancer other than breast cancer, and no mutation was detected among breast cancer females with no family history of any cancer or among normal control females. Screening mutations within exon 2, exon 11 and exon 20 showed that most screened mutations were within BRCA1 exon 11 among breast cancer Jordanian families with a family history of breast cancer. (author)

Polymorphisms rs12998 and rs5780218 in KiSS1 Suppressor Metastasis Gene in Mexican Patients with Breast Cancer

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Edhit Guadalupe Cruz Quevedo

2015-01-01

Full Text Available Aims. KiSS1 is a metastasis suppressor gene associated with inhibition of cellular chemotaxis and invasion attenuating the metastasis in melanoma and breast cancer cell lines. Along the KiSS-1 gene at least 294 SNPs have been described; however the association of these polymorphisms as genetic markers for metastasis in breast cancer studies has not been investigated. Here we describe two simple PCR-RFLPs protocols to identify the rs5780218 (9DelT and the rs12998 (E20K KiSS1 polymorphisms and the allelic, genotypic, and haplotypic frequencies in Mexican general population (GP and patients with benign breast disease (BBD or breast cancer (BC. Results. The rs5780218 polymorphism was individually associated with breast cancer (P=0.0332 and the rs12998 polymorphism shows statistically significant differences when GP versus case (BC and BBD groups were compared (P<0.0001. The H1 Haplotype (G/- occurred more frequently in BC group (0.4256 whereas H2 haplotype (G/T was the most prevalent in BBD group (0.4674. Conclusions. Our data indicated that the rs5780218 polymorphism individually confers susceptibility for development of breast cancer in Mexican population and a possible role as a genetic marker in breast cancer metastasis for H1 haplotype (Wt/variant in KiSS1 gene must be analyzed in other populations.

Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer.

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Kuo, Wen-Hong; Lin, Po-Han; Huang, Ai-Chu; Chien, Yin-Hsiu; Liu, Tsang-Pai; Lu, Yen-Shen; Bai, Li-Yuan; Sargeant, Aaron M; Lin, Ching-Hung; Cheng, Ann-Lii; Hsieh, Fon-Jou; Hwu, Wuh-Liang; Chang, King-Jen

2012-02-01

Although evidence suggests an importance of genetic factors in the development of breast cancer in Taiwanese (ethnic Chinese) women, including a high incidence of early-onset and secondary contralateral breast cancer, a major breast cancer predisposition gene, BRCA1, has not been well studied in this population. In fact, the carcinogenic impacts of many genetic variants of BRCA1 are unknown and classified as variants of uncertain significance (VUS). It is therefore important to establish a method to characterize the BRCA1 VUSs and understand their role in Taiwanese breast cancer patients. Accordingly, we developed a multimodel assessment strategy consisting of a prescreening portion and a validated functional assay to study breast cancer patients with early-onset, bilateral or familial breast cancer. We found germ-line BRCA1 mutations in 11.1% of our cohort and identified one novel missense mutation, c.5191C>A. Two genetic variants were initially classified as VUSs (c.1155C>T and c.5191C>A). c.1155C>T is not predicted to be deleterious in the prescreening portion of our assessment strategy. c.5191C>A, on the other hand, causes p.T1691K, which is predicted to have high deleterious probability because of significant structural alteration, a high deleterious score in the predictive programs and, clinically, triple negative characteristics in breast tumors. This mutant is confirmed by transcription activation and yeast growth-inhibition assays. In conclusion, we show as high a prevalence of germ-line BRCA1 mutation in high-risk Taiwanese patients as in Caucasians and demonstrate a useful strategy for studying BRCA1 VUSs.

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

Science.gov (United States)

Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

2018-01-01

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.

Association between breast cancer, breast density, and body adiposity evaluated by MRI

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Zhu, Wenlian; Huang, Peng; Macura, Katarzyna J.; Artemov, Dmitri

2016-01-01

Despite the lack of reliable methods with which to measure breast density from 2D mammograms, numerous studies have demonstrated a positive association between breast cancer and breast density. The goal of this study was to study the association between breast cancer and body adiposity, as well as breast density quantitatively assessed from 3D MRI breast images. Breast density was calculated from 3D T1-weighted MRI images. The thickness of the upper abdominal adipose layer was used as a surrogate marker for body adiposity. We evaluated the correlation between breast density, age, body adiposity, and breast cancer. Breast density was calculated for 410 patients with unilateral invasive breast cancer, 73 patients with ductal carcinoma in situ (DCIS), and 361 controls without breast cancer. Breast density was inversely related to age and the thickness of the upper abdominal adipose layer. Breast cancer was only positively associated with body adiposity and age. Age and body adiposity are predictive of breast density. Breast cancer was not associated with breast density; however, it was associated with the thickness of the upper abdominal adipose layer, a surrogate marker for body adiposity. Our results based on a limited number of patients warrant further investigations. (orig.)

Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.

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Cameron M Scott

Full Text Available DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.

Association of CYP1B1 Polymorphisms with Breast Cancer: A Case-Control Study in the Han Population in Ningxia Hui Autonomous Region, P. R. China

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Jiao, Haiyan; Liu, Chunlian; Guo, Weidong; Peng, Liang; Chen, Yintao; Martin, Francis L.

2010-01-01

Studies investigating possible associations between cytochrome P4501B1 (CYP1B1) polymorphisms and breast cancer risk have been inconsistent. We set out to ascertain whether there might be an association between polymorphisms in exon 2 (codon 119, G→T) and exon 3 (codon 432, G→C) of CYP1B1 and breast cancer in a Chinese Han population in the rural region of Ningxia. Using an allele-specific polymerase chain reaction method and direct DNA sequencing, the presence or absence of the two CYP1B1 polymorphisms was investigated. Genotype and allele frequencies were analyzed in breast cancer cases (n = 152) and healthy age-matched controls (n = 156). The odds ratio (OR) of 119G→T or 432G→C in breast cancer cases and controls was 3.3 (95% CI: 1.28 to 8.28) and 2.8 (95% CI: 1.04 to 7.51), respectively. In addition, the OR for people with both polymorphisms (119T and 432C) was 4.69 (95% CI: 1.97 to 11.19). Our results suggest that certain polymorphisms in the CYP1B1 gene might increase risk for breast cancer among Han Chinese, perhaps because they influence the efficiency of CYP1B1 bio-transformation of oestrogens or pro-carcinogens into DNA-reactive electrophiles that may act as cancer-initiating agents. PMID:20212917

IMMUNOPHENOTYPIC CHARACTERISTICS OF INFLAMMATORY BREAST CANCER

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A. I. Berishvili

2009-01-01

Full Text Available The investigation enrolled 31 patients with inflammatory breast cancer (IBC treated at the N. N. Blokhin Cancer Research Center from 2006 to 2008. IBC is diagnosed on the basis of signs of rapid progression, such as localized or generalized breast induration, red- ness and edema. IBC accounts for less than 5% of all diagnosed breast cancers and is the most lethal form of primary breast cancer. We studied tumor markers of the immunophenotype of IBC and levels and subpopulations of immunocompetent tumor-infiltrating cells. We found that expression of HLA-DR is in negative correlation with MUC-1 expression and lymphoid cells tumor infiltration is asso- ciated with the increase in T-cell subpopulations.

Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families : high cancer incidence at older age

NARCIS (Netherlands)

van der Kolk, Dorina M.; de Bock, Geertruida H.; Leegte, Beike K.; Schaapveld, Michael; Mourits, Marian J. E.; de Vries, J; van der Hout, Annemieke H.; Oosterwijk, Jan C.

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the

Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.

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Ana Blanco

Full Text Available BACKGROUND: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. METHODS: 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. RESULTS: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop previously reported, and c.3362del (p.Gly1121ValfsX3 which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. CONCLUSIONS: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s involved in the development of breast/pancreatic cancer families is required.

19p13.1 is a triple-negative-specific breast cancer susceptibility locus

DEFF Research Database (Denmark)

Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M

2012-01-01

(PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly......The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor...... associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER...

Mechanisms of Twist 1-Induced Invasion in Breast Cancer Metastasis

Science.gov (United States)

2011-01-01

affect breast cancer metastasis with a subcutaneous mouse tumor implantation model of breast cancer metastasis. HMLE -Twist1 cells expressing shRNAs...13 4 Introduction Distant metastases are responsible for the vast majority of breast cancer deaths. This process...to migrate and invade is therefore essential to the metastatic process. The initial steps of breast cancer metastasis, local invasion and

A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer.

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Dorairaj, Jemima J; Salzman, David W; Wall, Deirdre; Rounds, Tiffany; Preskill, Carina; Sullivan, Catherine A W; Lindner, Robert; Curran, Catherine; Lezon-Geyda, Kim; McVeigh, Terri; Harris, Lyndsay; Newell, John; Kerin, Michael J; Wood, Marie; Miller, Nicola; Weidhaas, Joanne B

2014-06-10

A germline, variant in the BRCA1 3'UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3'UTR mutations in cancer. The impact of the BRCA1-3'UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3'UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Luciferase reporters with the BRCA1-3'UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3'UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3'UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR=1.4, 95% CI 1.1-1.8, p=0.033). More importantly, patients with the BRCA1-3'UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p=0.018, OR=3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3'UTR-variant had significantly less dense breasts (p=0.0398) in the Vermont cohort. A variant in

SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes

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Markus D. Lacher

2018-05-01

Full Text Available Targeted cancer immunotherapy with irradiated, granulocyte–macrophage colony-stimulating factor (GM-CSF-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862, a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB, in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B, ADA (encoding adenosine deaminase, ADGRE5 (CD97, CD58 (LFA3, CD74 (encoding invariant chain and CLIP, CD83, CXCL8 (IL8, CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele treated with

BP1 Homeoprotein Enhances Metastatic Potential in Er-Negative Breast Cancer

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Yebo Fu, Yi Lian, Kyung Soon Kim, Lei Zhang, A. Katharine Hindle, Fred Brody, Robert S. Siegel, Timothy A. McCaffrey, Sidney W. Fu

2010-01-01

Full Text Available Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER- tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. I sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p<0.005, and enhanced the in vitro invasive activity by 25-65 fold (p<0.001. Microarray experiments were performed to identify differentially expressed genes when BP1 is overexpressed. The gene expression profile of the transfected cell lines were compared, resulting in 71 differentially expressed genes with a fold-change of >=2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Significant pathways were identified involving cell proliferation and metastasis. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target.

Immunolocalisation of members of the polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T) family is consistent with biologically relevant altered cell surface glycosylation in breast cancer

DEFF Research Database (Denmark)

Brooks, Susan A; Carter, Tracey M; Bennett, Eric P

2007-01-01

understood, may mediate the synthesis of varied glycoforms of cellular proteins with different biological activities. Disruptions in glycosylation are a common feature of cancer and may have functional significance. Immunocytochemistry with confocal scanning laser microscopy was employed to detect members...... of the ppGalNAc-T family, ppGalNAc-T1, -T2, -T3, -T4 and -T6 in a range of breast cell lines. The cells were chosen to represent a range of phenotypes from 'normal'/benign (HMT 3,522), primary, non-metastatic breast cancer (BT 474), to aggressive, metastatic breast cancer (ZR75-1, T47D, MCF-7, DU 4...... tightly restricted ppGalNAc-T's may result in initiation of O-linked glycosylation at normally unoccupied potential glycosylation sites leading to altered glycoforms of proteins with changed biological activity which may contribute to the pathogenesis of cancer....

Locoregional Recurrence Risk for Patients With T1,2 Breast Cancer With 1-3 Positive Lymph Nodes Treated With Mastectomy and Systemic Treatment

International Nuclear Information System (INIS)

McBride, Andrew; Allen, Pamela; Woodward, Wendy; Kim, Michelle; Kuerer, Henry M.; Drinka, Eva Katherine; Sahin, Aysegul; Strom, Eric A.; Buzdar, Aman; Valero, Vicente; Hortobagyi, Gabriel N.; Hunt, Kelly K.; Buchholz, Thomas A.

2014-01-01

Purpose: Postmastectomy radiation therapy (PMRT) has been shown to benefit breast cancer patients with 1 to 3 positive lymph nodes, but it is unclear how modern changes in management have affected the benefits of PMRT. Methods and Materials: We retrospectively analyzed the locoregional recurrence (LRR) rates in 1027 patients with T1,2 breast cancer with 1 to 3 positive lymph nodes treated with mastectomy and adjuvant chemotherapy with or without PMRT during an early era (1978-1997) and a later era (2000-2007). These eras were selected because they represented periods before and after the routine use of sentinel lymph node surgery, taxane chemotherapy, and aromatase inhibitors. Results: 19% of 505 patients treated in the early era and 25% of the 522 patients in the later era received PMRT. Patients who received PMRT had significantly higher-risk disease features. PMRT reduced the rate of LRR in the early era cohort, with 5-year rates of 9.5% without PMRT and 3.4% with PMRT (log-rank P=.028) and 15-year rates 14.5% versus 6.1%, respectively; (Cox regression analysis: adjusted hazard ratio [AHR] 0.37, P=.035). However, PMRT did not appear to benefit patients treated in the later cohort, with 5-year LRR rates of 2.8% without PMRT and 4.2% with PMRT (P=.48; Cox analysis: AHR 1.41, P=.48). The most significant factor predictive of LRR for the patients who did not receive PMRT was the era in which the patient was treated (AHR 0.35 for later era, P<.001). Conclusion: The risk of LRR for patients with T1,2 breast cancer with 1 to 3 positive lymph nodes treated with mastectomy and systemic treatment is highly dependent on the era of treatment. Modern treatment advances and the selected use of PMRT for those with high-risk features have allowed for identification of a cohort at very low risk for LRR without PMRT

Locoregional Recurrence Risk for Patients With T1,2 Breast Cancer With 1-3 Positive Lymph Nodes Treated With Mastectomy and Systemic Treatment

Energy Technology Data Exchange (ETDEWEB)

McBride, Andrew [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); University of Arizona School of Medicine, Phoenix, Arizona (United States); Allen, Pamela; Woodward, Wendy; Kim, Michelle [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kuerer, Henry M. [Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Drinka, Eva Katherine; Sahin, Aysegul [Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Strom, Eric A. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Buzdar, Aman; Valero, Vicente; Hortobagyi, Gabriel N. [Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hunt, Kelly K. [Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Buchholz, Thomas A., E-mail: tbuchhol@mdanderson.org [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2014-06-01

Purpose: Postmastectomy radiation therapy (PMRT) has been shown to benefit breast cancer patients with 1 to 3 positive lymph nodes, but it is unclear how modern changes in management have affected the benefits of PMRT. Methods and Materials: We retrospectively analyzed the locoregional recurrence (LRR) rates in 1027 patients with T1,2 breast cancer with 1 to 3 positive lymph nodes treated with mastectomy and adjuvant chemotherapy with or without PMRT during an early era (1978-1997) and a later era (2000-2007). These eras were selected because they represented periods before and after the routine use of sentinel lymph node surgery, taxane chemotherapy, and aromatase inhibitors. Results: 19% of 505 patients treated in the early era and 25% of the 522 patients in the later era received PMRT. Patients who received PMRT had significantly higher-risk disease features. PMRT reduced the rate of LRR in the early era cohort, with 5-year rates of 9.5% without PMRT and 3.4% with PMRT (log-rank P=.028) and 15-year rates 14.5% versus 6.1%, respectively; (Cox regression analysis: adjusted hazard ratio [AHR] 0.37, P=.035). However, PMRT did not appear to benefit patients treated in the later cohort, with 5-year LRR rates of 2.8% without PMRT and 4.2% with PMRT (P=.48; Cox analysis: AHR 1.41, P=.48). The most significant factor predictive of LRR for the patients who did not receive PMRT was the era in which the patient was treated (AHR 0.35 for later era, P<.001). Conclusion: The risk of LRR for patients with T1,2 breast cancer with 1 to 3 positive lymph nodes treated with mastectomy and systemic treatment is highly dependent on the era of treatment. Modern treatment advances and the selected use of PMRT for those with high-risk features have allowed for identification of a cohort at very low risk for LRR without PMRT.

Omission of Breast Radiotherapy in Low-risk Luminal A Breast Cancer: Impact on Health Care Costs.

Science.gov (United States)

Han, K; Yap, M L; Yong, J H E; Mittmann, N; Hoch, J S; Fyles, A W; Warde, P; Gutierrez, E; Lymberiou, T; Foxcroft, S; Liu, F F

2016-09-01

The economic burden of cancer care is substantial, including steep increases in costs for breast cancer management. There is mounting evidence that women age ≥ 60 years with grade I/II T1N0 luminal A (ER/PR+, HER2- and Ki67 ≤ 13%) breast cancer have such low local recurrence rates that adjuvant breast radiotherapy might offer limited value. We aimed to determine the total savings to a publicly funded health care system should omission of radiotherapy become standard of care for these patients. The number of women aged ≥ 60 years who received adjuvant radiotherapy for T1N0 ER+ HER2- breast cancer in Ontario was obtained from the provincial cancer agency. The cost of adjuvant breast radiotherapy was estimated through activity-based costing from a public payer perspective. The total saving was calculated by multiplying the estimated number of luminal A cases that received radiotherapy by the cost of radiotherapy minus Ki-67 testing. In 2010, 748 women age ≥ 60 years underwent surgery for pT1N0 ER+ HER2- breast cancer; 539 (72%) underwent adjuvant radiotherapy, of whom 329 were estimated to be grade I/II luminal A subtype. The cost of adjuvant breast radiotherapy per case was estimated at $6135.85; the cost of Ki-67 at $114.71. This translated into an annual saving of about $2.0million if radiotherapy was omitted for all low-risk luminal A breast cancer patients in Ontario and $5.1million across Canada. There will be significant savings to the health care system should omission of radiotherapy become standard practice for women with low-risk luminal A breast cancer. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

RAD51B in Familial Breast Cancer.

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Liisa M Pelttari

Full Text Available Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC that were genotyped on a custom chip (iCOGS. We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259 and population controls (n = 3586 from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR: 1.15, 95% confidence interval (CI: 1.11-1.19, P = 8.88 x 10-16 and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11, compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

RAD51B in Familial Breast Cancer

Science.gov (United States)

Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Dörk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Dunning, Alison M.; García-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; Benitez, Javier; González-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Brüning, Thomas; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Van Dyck, Laurien; Janssen, Hilde; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Hallberg, Emily; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Dumont, Martine; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Devilee, Peter; Seynaeve, Caroline; Hooning, Maartje J.; Collée, Margriet; Cox, Angela; Cross, Simon S.; Shah, Mitul; Luben, Robert N.; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Couch, Fergus J.; Yannoukakos, Drakoulis; Orr, Nick; Swerdlow, Anthony; Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per; Easton, Douglas F.; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. PMID:27149063

Relationship Between Mutations In BRCA1 And BRCA2 Genes And Breast Cancer Prevalence Among Egyptian Women

International Nuclear Information System (INIS)

ELMAGHRABY, T.K.

2009-01-01

Breast cancer represents the most common cancer of women in the world and it is a biologically heterogeneous disease influenced by complex interactions between multiple genetic and environmental risk factors. In Egypt, breast cancer is classified as the first rank cancer case among women. The present study included 55 patients with breast cancer from Upper Egypt of which 40 patients had sporadic and 15 had familial breast cancers. Mutations in DNA of exons 10 and 11 of BRCA1 and BRCA2 were detected by single strand conformation polymorphisms (SSCPs) and sequencing. Moreover, BRCA1 protein expression was detected by immunostaining technique and correlation between risk factors and incidence rate of breast cancer. The results revealed 5 mutations (unclassified variants); three mutations (60%) were recorded internationally in Breast Information Cancer (BIC), one of them was 1767 C→T(550 Asn→His) and previously recorded in the Arabic world and the other 2 novel mutations were 1663 T→ C(479 Asp→Gly) and del AG 6079. The results obtained in the present study also demonstrated that the increase of the negative immunostaining of ''BRCA1'' protein in the tumour cells of BRCA1 mutation carriers was comparable to familial and sporadic breast cancer non-carrier. Accurate estimation of the relative frequency of BRCA1 and BRCA2 mutations in Egyptian breast cancer patients could not be deduced from the results of this relatively small pilot study. More studies with larger numbers of patients are needed to clarify the relation between BRCA1 and BRCA2 gene mutations and the prediction of breast cancer in Egypt.

Is Biological Subtype Prognostic of Locoregional Recurrence Risk in Women With pT1-2N0 Breast Cancer Treated With Mastectomy?

International Nuclear Information System (INIS)

Truong, Pauline T.; Sadek, Betro T.; Lesperance, Maria F.; Alexander, Cheryl S.; Shenouda, Mina; Raad, Rita Abi; Taghian, Alphonse G.

2014-01-01

Purpose: To examine locoregional and distant recurrence (LRR and DR) in women with pT1-2N0 breast cancer according to approximated subtype and clinicopathologic characteristics. Methods and Materials: Two independent datasets were pooled and analyzed. The study participants were 1994 patients with pT1-2N0M0 breast cancer, treated with mastectomy without radiation therapy. The patients were classified into 1 of 5 subtypes: luminal A (ER+ or PR+/HER 2−/grade 1-2, n=1202); luminal B (ER+ or PR+/HER 2−/grade 3, n=294); luminal HER 2 (ER+ or PR+/HER 2+, n=221); HER 2 (ER−/PR−/HER 2+, n=105) and triple-negative breast cancer (TNBC) (ER−/PR−/HER 2−, n=172). Results: The median follow-up time was 4.3 years. The 5-year Kaplan-Meier (KM) LRR were 1.8% in luminal A, 3.1% in luminal B, 1.7% in luminal HER 2, 1.9% in HER 2, and 1.9% in TNBC cohorts (P=.81). The 5-year KM DR was highest among women with TNBC: 1.8% in luminal A, 5.0% in luminal B, 2.4% in luminal HER 2, 1.1% in HER 2, and 9.6% in TNBC cohorts (P 2 cm, lobular histology, and close/positive surgical margins. Conclusions: The 5-year risk of LRR in our pT1-2N0 cohort treated with mastectomy was generally low, with no significant differences observed between approximated subtypes. Among the subtypes, TNBC conferred the highest risk of DR and an elevated risk of LRR in the presence of positive or close margins. Our data suggest that although subtype alone cannot be used as the sole criterion to offer postmastectomy radiation therapy, it may reasonably be considered in conjunction with other clinicopathologic factors including tumor size, histology, and margin status. Larger cohorts and longer follow-up times are needed to define which women with node-negative disease have high postmastectomy LRR risks in contemporary practice

Postmastectomy Radiation Therapy in Women with T1-T2 Tumors and 1 to 3 Positive Lymph Nodes: Analysis of the Breast International Group 02-98 Trial.

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Zeidan, Youssef H; Habib, Joyce G; Ameye, Lieveke; Paesmans, Marianne; de Azambuja, Evandro; Gelber, Richard D; Campbell, Ian; Nordenskjöld, Bo; Gutiérez, Jorge; Anderson, Michael; Lluch, Ana; Gnant, Michael; Goldhirsch, Aron; Di Leo, Angelo; Joseph, David J; Crown, John; Piccart-Gebhart, Martine; Francis, Prudence A

2018-06-01

To analyze the impact of postmastectomy radiation therapy (PMRT) for patients with T1-T2 tumors and 1 to 3 positive lymph nodes enrolled on the Breast International Group (BIG) 02-98 trial. The BIG 02-98 trial randomized patients to receive adjuvant anthracycline with or without taxane chemotherapy. Delivery of PMRT was nonrandomized and performed according to institutional preferences. The present analysis was performed on participants with T1-T2 breast cancer and 1 to 3 positive lymph nodes who had undergone mastectomy and axillary nodal dissection. The primary objective of the present study was to examine the effect of PMRT on risk of locoregional recurrence (LRR), breast cancer-specific survival, and overall survival. We identified 684 patients who met the inclusion criteria and were included in the analysis, of whom 337 (49%) had received PMRT. At 10 years, LRR risk was 2.5% in the PMRT group and 6.5% in the no-PMRT group (hazard ratio 0.29, 95% confidence interval 0.12-0.73; P = .005). Lower LRR after PMRT was noted for patients randomized to receive adjuvant chemotherapy with no taxane (10-year LRR: 3.4% vs 9.1%; P = .02). No significant differences in breast cancer-specific survival (84.3% vs 83.9%) or overall survival (81.7% vs 78.3%) were observed according to receipt of PMRT. Our analysis of the BIG 02-98 trial shows excellent outcomes in women with T1-T2 tumors and 1 to 3 positive lymph nodes found in axillary dissection. Although PMRT improved LRR in this cohort, the number of events remained low at 10 years. In all groups, 10-year rates of LRR were relatively low compared with historical studies. As such, the use of PMRT in women with 1 to 3 positive nodes should be tailored to individual patient risks. Copyright © 2018 Elsevier Inc. All rights reserved.

For or against adjuvant trastuzumab for pT1a-bN0M0 breast cancer patients with HER2-positive tumors: a meta-analysis of published literatures.

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Qiong Zhou

Full Text Available BACKGROUND: Although the prognosis of patients with small (≤1cm tumors is generally favorable, emerging data suggests that biological behavior varies between intrinsic subtypes in such patients. Furthermore, it still remains unclear whether HER2-positive pT1a-bN0M0 patients could benefit from adjuvant trastuzumab. For further evaluation, we sought to conduct a meta-analysis so as to get a better understanding of the prognosis for HER2-positive pT1a-bN0M0 patients and their survival benefit from adjuvant trastuzumab, accordingly, offering the implications for current practice. METHODS: The PubMed database, the online proceedings of the American Society of Clinical Oncology (ASCO Annual Meetings, the online proceedings of the San Antonio Breast Cancer Symposium, and the CD proceedings of the International St. Gallen Breast Cancer Conference were searched for all relevant studies published before September 2012. Relative risks (RRs were used to compare the prognosis of different intrinsic subtypes for pT1a-bN0M0 breast cancer. Analyses were also performed to estimate the association between adjuvant trastuzumab and various survival outcomes. RESULTS: With eight eligible studies identified, this meta-analysis demonstrated a deleterious effect of HER2+ phenotype on disease-free survival (DFS; RR = 3.677, 95% CI 2.606-5.189, p <0.001 and distant disease-free survival (DDFS; RR = 3.824, 95% CI 2.249-6.501, p<0.001 as compared to HR+/HER2- subgroup. However, significant difference failed to be achieved in terms of any endpoint between HER2+ and triple negative breast cancer (TNBC. Besides, a marked improvement in DFS was observed with the addition of trastuzumab for HER2-positive pT1a-bN0M0 patients (RR = 0.323, 95% CI 0.191-0.547, p<0.001. CONCLUSION: This meta-analysis clarifies that intrinsic subtypes might be a reliable marker to predict the prognosis in pT1a-bN0M0 breast cancer. Besides, even for such early stage HER2-positive

Cyclin D1, Id1 and EMT in breast cancer

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Tobin, Nicholas P; Sims, Andrew H; Lundgren, Katja L; Lehn, Sophie; Landberg, Göran

2011-01-01

Cyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1 and EMT, as well as clinical properties in primary breast cancer. Protein and gene expression of ID1, CCND1 and EMT markers were determined in MDA-MB-231 and ZR75 cells by western blot and qPCR. Cell migration and promoter occupancy were monitored by transwell and ChIP assays, respectively. Gene expression was analysed from publicly available datasets. The increase in cell migration following cyclin D1 silencing in MDA-MB-231 cells was abolished by Id1 siRNA treatment and we observed cyclin D1 occupancy of the Id1 promoter region. Moreover, ID1 and SNAI2 gene expression was increased following cyclin D1 knock-down, an effect reversed with Id1 siRNA treatment. Similar migratory and SNAI2 increases were noted for the ER-positive ZR75-1 cell line, but in an Id1-independent manner. In a meta-analysis of 1107 breast cancer samples, CCND1 low /ID1 high tumours displayed increased expression of EMT markers and were associated with reduced recurrence free survival. Finally, a greater percentage of CCND1 low /ID1 high tumours were found in the EMT-like 'claudin-low' subtype of breast cancer than in other subtypes. These results indicate that increased migration of MDA-MB-231 cells following cyclin D1 silencing can be mediated by Id

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers

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Jakubowska, A; Rozkrut, D; Antoniou, A

2012-01-01

The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or...

BRCA1 status in Pakistani breast cancer patients with moderate family history

International Nuclear Information System (INIS)

Moatter, T.; Pervez, S.; Khan, S.; Azam, I.

2011-01-01

Objective: To determine BRCA1 status in breast carcinoma patients of Pakistani origin. Study Design: Observational study. Place and Duration of Study: The Oncology Clinics of the Aga Khan University Hospital, Karachi, between May 2005 and December 2009. Methodology: Fifty three breast cancer patients based on clinical and laboratory diagnosis were recruited for this study. Moderate family history was defined as having a close relative (mother, daughter, sister) diagnosed with breast cancer under 45 years. Peripheral blood samples were collected from each patient in a 5 ml tube containing EDTA as anticoagulant. Subsequent to DNA extraction, mutational analysis of BRCA1 exons 2, 5, 6, 16, 20 and 22 was carried out using single strand conformation polymorphism (SSCP) assay while protein truncation test (PTT) was used to examine mutations in exon 11. All BRCA1 sequence variants were confirmed by DNA sequencing. Results: Twenty-three patients were diagnosed with early onset breast cancer, 30 patients had moderate family history. At the time of diagnosis, the median age of enrolled patients was 39 years (range 24-65 years). Out of 53 patients, analyzed by SSCP assay, mobility shift was detected in exon 6, 16 and 20 of three patients, whereas one patient was tested positive for mutation in exon 11 by PTT assays. All patients with BRCA1 mutations were further confirmed by DNA sequencing analysis. In exon 16 c.4837A > G was confirmed, which is a common polymorphism reported in several populations including Asians. Moreover, mutations in exon 6 (c.271T > G), exon 20 (c.5231 del G) and exon 11 (c.1123 T > G) were reported first time in the Pakistani population. Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. Therefore, mutation-based genetic counselling for patients with moderate family history can facilitate management, if one first or second degree relative or early onset disease is apparent. (author)

Myeloid-derived suppressor cells in breast cancer.

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Markowitz, Joseph; Wesolowski, Robert; Papenfuss, Tracey; Brooks, Taylor R; Carson, William E

2013-07-01

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.

Dichotomous roles for the orphan nuclear receptor NURR1 in breast cancer

International Nuclear Information System (INIS)

Llopis, Shawn; Singleton, Brittany; Duplessis, Tamika; Carrier, Latonya; Rowan, Brian; Williams, Christopher

2013-01-01

NR4A orphan nuclear receptors are involved in multiple biological processes which are important in tumorigenesis such as cell proliferation, apoptosis, differentiation, and glucose utilization. The significance of NR4A family member NURR1 (NR4A2) in breast cancer etiology has not been elucidated. The purpose of this study was to ascertain the impact of NURR1 expression on breast transformation, tumor growth, and breast cancer patient survival. We determined the expression of NURR1 in normal breast versus breast carcinoma in tissue microarrays (immunohistochemistry), tissue lysates (immunoblot), and at the mRNA level (publically available breast microarrays). In addition NURR1 expression was compared among breast cancer patients in cohorts based on p53 expression, estrogen receptor α expression, tumor grade, and lymph node metastases. Kaplan-Meier survival plots were used to determine the correlation between NURR1 expression and relapse free survival (RFS). Using shRNA-mediated silencing, we determined the effect of NURR1 expression on tumor growth in mouse xenografts. Results from breast cancer tissue arrays demonstrate a higher NURR1 expression in the normal breast epithelium compared to breast carcinoma cells (p ≤ 0.05). Among cases of breast cancer, NURR1 expression in the primary tumors was inversely correlated with lymph node metastases (p ≤ 0.05) and p53 expression (p ≤ 0.05). Clinical stage and histological grade were not associated with variation in NURR1 expression. In gene microarrays, 4 of 5 datasets showed stronger mean expression of NURR1 in normal breast as compared to transformed breast. Additionally, NURR1 expression was strongly correlated with increase relapse free survival (HR = 0.7) in a cohort of all breast cancer patients, but showed no significant difference in survival when compared among patients whom have not been treated systemically (HR = 0.91). Paradoxically, NURR1 silenced breast xenografts showed significantly decreased growth

Genetic variants in TGFβ-1 and PAI-1 as possible risk factors for cardiovascular disease after radiotherapy for breast cancer

International Nuclear Information System (INIS)

Hilbers, Florentine S.M.; Boekel, Naomi B.; Broek, Alexandra J. van den; Hien, Richard van; Cornelissen, Sten; Aleman, Berthe M.P.; Veer, Laura J. van’t; Leeuwen, Flora E. van; Schmidt, Marjanka K.

2012-01-01

Background and purpose: It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFβ pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFβ1 29C > T and PAI-1 5G > 4G, on CVD incidence. Materials and methods: This retrospective cohort study included 422 10-year breast cancer survivors, aged 4G and CVD risk. Conclusion: Our study suggests there might be an association between the TGFβ1 29C > T polymorphism and CVD risk in long-term breast cancer survivors.

Common breast cancer susceptibility loci are associated with triple negative breast cancer

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Stevens, Kristen N.; Vachon, Celine M.; Lee, Adam M.; Slager, Susan; Lesnick, Timothy; Olswold, Curtis; Fasching, Peter A.; Miron, Penelope; Eccles, Diana; Carpenter, Jane E.; Godwin, Andrew K.; Ambrosone, Christine; Winqvist, Robert; Schmidt, Marjanka K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor; Hartmann, Arndt; Beckmann, Matthias W.; Schulz-Wendtland, Rüdiger; Ekici, Arif B.; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Graham, Nikki; Hein, Rebecca; Nickels, Stephan; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Hans-Peter; Konstantopoulou, Irene; Fostira, Florentia; Pectasides, Dimitrios; Dimopoulos, Athanasios M.; Fountzilas, George; Clarke, Christine L.; Balleine, Rosemary; Olson, Janet E.; Fredericksen, Zachary; Diasio, Robert B.; Pathak, Harsh; Ross, Eric; Weaver, JoEllen; Rüdiger, Thomas; Försti, Asta; Dünnebier, Thomas; Ademuyiwa, Foluso; Kulkarni, Swati; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Ko, Yon-Dschun; Van Limbergen, Erik; Janssen, Hilde; Peto, Julian; Fletcher, Olivia; Giles, Graham G.; Baglietto, Laura; Verhoef, Senno; Tomlinson, Ian; Kosma, Veli-Matti; Beesley, Jonathan; Greco, Dario; Blomqvist, Carl; Irwanto, Astrid; Liu, Jianjun; Blows, Fiona M.; Dawson, Sarah-Jane; Margolin, Sara; Mannermaa, Arto; Martin, Nicholas G.; Montgomery, Grant W; Lambrechts, Diether; dos Santos Silva, Isabel; Severi, Gianluca; Hamann, Ute; Pharoah, Paul; Easton, Douglas F.; Chang-Claude, Jenny; Yannoukakos, Drakoulis; Nevanlinna, Heli; Wang, Xianshu; Couch, Fergus J.

2012-01-01

Triple negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiological factors which promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome wide association studies (GWAS) display heterogeneity of effect among breast cancer subtypes as defined by estrogen receptor (ER) and progesterone receptor (PR) status. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple negative breast cancer and 4,978 healthy controls. We identified six single nucleotide polymorphisms (SNPs) significantly associated with risk of triple negative breast cancer, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.11) and rs8100241 (19p13.11). Together, our results provide convincing evidence of genetic susceptibility for triple negative breast cancer. PMID:21844186

High ASMA+ Fibroblasts and Low Cytoplasmic HMGB1+ Breast Cancer Cells Predict Poor Prognosis.

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Amornsupak, Kamolporn; Jamjuntra, Pranisa; Warnnissorn, Malee; O-Charoenrat, Pornchai; Sa-Nguanraksa, Doonyapat; Thuwajit, Peti; Eccles, Suzanne A; Thuwajit, Chanitra

2017-10-01

The influence of cancer-associated fibroblasts (CAFs) and high mobility group box 1 (HMGB1) has been recognized in several cancers, although their roles in breast cancer are unclear. The present study aimed to determine the levels and prognostic significance of α-smooth muscle actin-positive (ASMA + ) CAFs, plus HMGB1 and receptor for advanced glycation end products (RAGE) in cancer cells. A total of 127 breast samples, including 96 malignant and 31 benign, were examined for ASMA, HMGB1, and RAGE by immunohistochemistry. The χ 2 test and Fisher's exact test were used to test the association of each protein with clinicopathologic parameters. The Kaplan-Meier method or log-rank test and Cox regression were used for survival analysis. ASMA + fibroblast infiltration was significantly increased in the tumor stroma compared with that in benign breast tissue. The levels of cytoplasmic HMGB1 and RAGE were significantly greater in the breast cancer tissue than in the benign breast tissues. High ASMA expression correlated significantly with large tumor size, clinical stage III-IV, and angiolymphatic and perinodal invasion. In contrast, increased cytoplasmic HMGB1 correlated significantly with small tumor size, pT stage, early clinical stage, luminal subtype (but not triple-negative subtype), and estrogen receptor and progesterone receptor expression. The levels of ASMA (hazard ratio, 14.162; P = .010) and tumor cytoplasmic HMGB1 (hazard ratio, 0.221; P = .005) could serve as independent prognostic markers for metastatic relapse in breast cancer patients. The ASMA-high/HMGB1-low profile provided the most reliable prediction of metastatic relapse. We present for the first time, to the best of our knowledge, the potential clinical implications of the combined assessment of ASMA + fibroblasts and cytoplasmic HMGB1 in breast cancer. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

BRCA1 and TP53 Gene-Mutations: Family Predisposition and Radioecological Risk of Developing Breast Cancer.

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Apsalikov, Bakytbek; Manambaeva, Zukhra; Ospanov, Erlan; Massabayeva, Meruyert; Zhabagin, Kuantkan; Zhagiparova, Zhanar; Maximov, Vladymir; Voropaeva, Elena; Apsalikov, Kazbek; Belikhina, Tatiana; Abdrahmanov, Ramil; Cherepkova, Elena; Tanatarov, Sayat; Massadykov, Adilzhan; Urazalina, Naylia

2016-01-01

Frequencies of polymorphisms of genes BRCA1 and TP53 in breast cancer (BC) patients with a BC family history and radiation history were assessed and compared in the Semey region of Kazakhstan. The study included 60 women directly irradiated by the activities of the Semipalatinsk test site with a calculated effective equivalent dose of 500 mSv and their first generation descendants (group BC+Her+Exp); 65 women with family BC and absence of radiological history - the effective equivalent dose due to anthropogenic sources not exceeding 50 mSv (group BC+Her-Exp). The comparison group consisted of 65 women patients with breast cancer without family and radiological history (BC-Her-Exp). The control group comprised 60 women without breast cancer and without family and radiological history (nonBC). We carried out the genotyping of the polymorphisms c.2311T>C, c.4308T>C and 5382insC of the BRCA1 gene and rs1042522 of the TP53 gene. The frequency of the polymorphism c.2311T>C was significantly higher in patients of the group BC+Her+Exp than in healthy women, and of the polymorphism 5382insC in BC+Her+Exp compared to all other groups. The frequency of the rs1042522 polymorphism of TP53 was significantly higher in all groups of patients with breast cancer compared with the control group. Differences between groups of women with breast cancer were significant only in BC+Her+Exp vs. BC+Her-Exp. Combinations of polymorphisms of the genes BRCA1 and TP53 predominated in women with a family and radiological history.

Efficacy of storage phosphor-based digital mammography in diagnosis of breast cancer

International Nuclear Information System (INIS)

Kitahama, Hiroyuki

1991-01-01

The aim of this study is to present efficacy of storage phosphor-based digital mammography (CR-mammography) in diagnosis of breast cancer. Ninety-seven cases with breast cancer including 44 cases less than 2 cm in macroscopic size (t1 cases) were evaluated using storage phosphor-based digital mammography (2000 x 2510 pixels by 10 bits). Abnormal findings on CR-mammography were detected in 86 cases (88.7%) of 97 women with breast cancer. Sensitivity of CR-mammography was 88.7%. It was superior to that of film-screen mammography. On t1 breast cancer cases, sensitivity on CR-mammography was 88.6%. False negative rate in t1 breast cancer cases was reduced by image processing using CR-mammography. To evaluate microcalcifications, CR-mammograms and film-screen mammograms were investigated in 22 cases of breast cancer proven pathologically the existence of microcalcifications and 11 paraffin tissue blocks of breast cancer. CR-mammography was superior to film-screen mammography in recognizing of microcalcifications. As regards the detectability for the number and the shape of microcalcifications, CR-mammography was equivalent to film-screen mammography. Receiver operating characteristic (ROC) analysis by eight observers was performed for CR-mammography and film-screen mammography with 54 breast cancer patients and 54 normal cases. The detectability of abnormal findings of breast cancer on CR-mammography (ROC area=0.91) was better than that on film-screen mammography (ROC area=0.88) (p<0.05). Efficacy of storage phosphor-based digital mammography in diagnosis of breast cancer was discussed and demonstrated in this study. (author)

Potential Biomarker of L type Amino Acid Transporter 1 in Breast Cancer Progression

International Nuclear Information System (INIS)

Liang, Zhongxing; Cho, Heidi T.; Williams, Larry; Zhu, Aizhi; Liang, Ke; Huang, Ke; Wu, Hui; Jiang, Chunsu; Hong, Samuel; Crowe, Ronald; Goodman, Mark M.; Shim, Hyunsuk

2011-01-01

L type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with 1 amino 3 [ 18F ]fluorocyclo butane 1 carboxylic acid ([ 18F ]FACBC) PET was assessed for its diagnostic biomarker potential. Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced stage breast cancer. Furtermore, the blockade of LAT1 with its inhibitor, 2 amino bicyclo[2.2.1]heptane 2 carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, [ 18F ]FACBC, has been demonstrated to be an excellent PET tracer for the non invasive imaging og malignant breast cancer using an orthotopic animal model. The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. [ 18F ]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging

Relationship of Predicted Risk of Developing Invasive Breast Cancer, as Assessed with Three Models, and Breast Cancer Mortality among Breast Cancer Patients.

Directory of Open Access Journals (Sweden)

Mark E Sherman

Full Text Available Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown.Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC for 37,939 invasive breast cancers (1996-2007, we estimated 5-year breast cancer risk (<1%; 1-1.66%; ≥1.67% with three models: BCSC 1-year risk model (BCSC-1; adapted to 5-year predictions; Breast Cancer Risk Assessment Tool (BCRAT; and BCSC 5-year risk model (BCSC-5. Breast cancer-specific mortality post-diagnosis (range: 1-13 years; median: 5.4-5.6 years was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified (35-44; 45-54; 55-69; 70-89 years models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years.Of 6,021 deaths, 2,993 (49.7% were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk ≥1.67% versus <1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR = 0.82 (95% CI = 0.75-0.90; BCRAT: HR = 0.72 (95% CI = 0.65-0.81 and BCSC-5: HR = 0.84 (95% CI = 0.75-0.94. Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55-69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35-44 years.Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering women counseling, it may be useful to note that high

Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

Directory of Open Access Journals (Sweden)

Nigel P S Crawford

2007-11-01

Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer.

Science.gov (United States)

Torkelson, Carolyn J; Sweet, Erin; Martzen, Mark R; Sasagawa, Masa; Wenner, Cynthia A; Gay, Juliette; Putiri, Amy; Standish, Leanna J

2012-01-01

Introduction. Orally administered preparations from the Trametes versicolor (Tv) mushroom have been hypothesized to improve immune response in women with breast cancer after standard chemotherapy and radiotherapy. Methods. A phase I, two-center, dose escalation study was done to determine the maximum tolerated dose of a Tv preparation when taken daily in divided doses for 6 weeks after recent completion of radiotherapy. Eleven participants were recruited and nine women completed the study. Each cohort was comprised of three participants given one of three doses of Tv (3, 6, or 9 grams). Immune data was collected pre- and postradiation, at 3 on-treatment time points and after a 3-week washout. Results. Nine adverse events were reported (7 mild, 1 moderate, and 1 severe), suggesting that Tv was well tolerated. Immunological results indicated trends in (1) increased lymphocyte counts at 6 and 9 grams/day; (2) increased natural killer cell functional activity at 6 grams/day; (3) dose-related increases in CD8(+) T cells and CD19(+) B cells , but not CD4(+) T cells or CD16(+)56(+) NK cells. Conclusion. These findings show that up to 9 grams/day of a Tv preparation is safe and tolerable in women with breast cancer in the postprimary treatment setting. This Tv preparation may improve immune status in immunocompromised breast cancer patients following standard primary oncologic treatment.

Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer.

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Mukherjee, Pinku; Madsen, Cathy S; Ginardi, Amelia R; Tinder, Teresa L; Jacobs, Fred; Parker, Joanne; Agrawal, Babita; Longenecker, B Michael; Gendler, Sandra J

2003-01-01

Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-gamma, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-beta2, and decrease in IFN-gamma -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches.

Relation of polymorphism C1236T and C3435T in ABCB1 gene with bone marrow suppression in chemotherapy-treated breast cancer patients

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Syarifah, S.; Hamdi, T.; Widyawati, T.; Sari, M. I.; Anggraini, D. R.

2018-03-01

ABCB1 is agene that encoded P-glycoprotein (P-gp), a transmembrane active efflux pump for a variety of carcinogens and cytostatics.ABCB1 polymorphisms C1236T and C3435T contribute to the variability oftherapeutic outcome and side effects.The present study was conducted to investigatethe relation of C1236T and C3435T polymorphisms in ABCB1 gene with bone marrow suppression in breast cancer patients treated withchemotherapy72 Indonesian womens isolated DNA sampleswere amplified using the PCR method. The analysis process of ABCB1 C1236T and C3435T polymorphism was by using thePCR-RFLP method. The frequencies of ABCB1 C1236T genotype for homozygous CC,heterozygous CT and variant TT was 11(15.28%), 42(58.33%), 19(26.39%), respectively. No associationwas between ABCB1 C1236T and C3435T polymorphisms in both individually and haplotypes with bone marrow suppression event (p > 0.05). There was no specific deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. There was a linkage between heterozygous CT-heterozygous CT in position 1236 and 3435 within 25 people (35%).

CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation.

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Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey; Sukumaran, Sujita; Watanabe, Norihiro; Hoyos, Valentina; Lulla, Premal; Brenner, Malcolm K; Leen, Ann M; Vera, Juan F

2018-05-10

The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site. First (1G - CD3ζ) and second generation (2G - 41BB.CD3ζ) MUC1-specific CARs were constructed using the HMFG2 scFv. Following retroviral transduction transgenic expression of the CAR±ICR was assessed by flow cytometry. In vitro CAR/ICR T cell function was measured by assessing cell proliferation and short- and long-term cytotoxic activity using MUC1+ MDA MB 468 cells as targets. In vivo anti-tumor activity was assessed using IL4-producing MDA MB 468 tumor-bearing mice using calipers to assess tumor volume and bioluminescence imaging to track T cells. In the IL4-rich tumor milieu, 1G CAR.MUC1 T cells failed to expand or kill MUC1+ tumors and while co-expression of the 4/7ICR promoted T cell expansion, in the absence of co-stimulatory signals the outgrowing cells exhibited an exhausted phenotype characterized by PD-1 and TIM3 upregulation and failed to control tumor growth. However, by co-expressing 2G CAR.MUC1 (signal 1 - activation + signal 2 - co-stimulation) and 4/7ICR (signal 3 - cytokine), transgenic T cells selectively expanded at the tumor site and produced potent and durable tumor control in vitro and in vivo. Our findings demonstrate the feasibility of targeting breast

Inhibition of Breast Cancer Metastasis by Heregulin-Beta 1

National Research Council Canada - National Science Library

Yu, Dihua

1999-01-01

The major goal of this Idea proposal is to determine whether and how HRG-Beta1 inhibits breast cancer metastasis and to identify the functional domains that are sufficient for inhibition of breast cancer metastasis...

Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

International Nuclear Information System (INIS)

Recondo, Gonzalo Jr; Vega, Maximo de la; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

2016-01-01

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

Directory of Open Access Journals (Sweden)

Simon N Stacey

2010-07-01

Full Text Available We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1 genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively. Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3, African (OR = 1.35, P = 0.014, and Asian (OR = 1.23, P = 2.9 x 10(-4 population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7, was without significant heterogeneity between ancestries (P(het = 0.36 and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268, which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

MicroRNA-384 inhibits the progression of breast cancer by targeting ACVR1.

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Wang, Yongxia; Zhang, Zheying; Wang, Jianqiang

2018-04-20

Breast cancer is the leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer cases and has a poorer prognosis than other subtypes. Moreover, the treatment for breast cancer, especially for TNBC, remains unsatisfactory. Therefore, novel therapies are urgently needed. Microribonucleic acids (miRNAs) are a class of biomarkers and therapeutic targets in many types of cancers. In the present study, the expression of miR-384 was explored in GSE58606 and in fresh breast cancer tissues by qPCR. The results showed that miR-384 was decreased in breast cancer, especially in TNBC. The results of MTT, colony formation, soft agar, Transwell migration, wound healing and the tumorigenesis assay demonstranted that overexpression of miR-384 inhibited the proliferation and migration of breast cancer in vitro and in vivo; knockdown of miR-384 enhanced the proliferation and migration of breast cancer. In addition, luciferase assay showed that Activin A receptor type 1 (ACVR1) was a direct target of miR-384 and is involved in the inhibitory effects of miR-384 on breast cancer progression. Furthermore, this study indicated that ACVR1 activated the Wnt/β-catenin signaling pathway in breast cancer. In conclusion, our findings revealed functional and mechanistic links between miR-384 and ACVR1 in the progression of breast cancer. miR-384 not only plays an important role in the progression of breast cancer, but has promise as a potential therapeutic target for breast cancer especially for TNBC.

Oestradiol reduces Liver Receptor Homolog-1 mRNA transcript stability in breast cancer cell lines

International Nuclear Information System (INIS)

Lazarus, Kyren A.; Zhao, Zhe; Knower, Kevin C.; To, Sarah Q.; Chand, Ashwini L.; Clyne, Colin D.

2013-01-01

Highlights: •LRH-1 is an orphan nuclear receptor that regulates tumor proliferation. •In breast cancer, high mRNA expression is associated with ER+ status. •In ER−ve cells, despite very low mRNA, we found abundant LRH-1 protein. •Our data show distinctly different LRH-1 protein isoforms in ER− and ER+ breast cancer cells. •This is due to differences in LRH-1 mRNA and protein stability rates. -- Abstract: The expression of orphan nuclear receptor Liver Receptor Homolog-1 (LRH-1) is elevated in breast cancer and promotes proliferation, migration and invasion in vitro. LRH-1 expression is regulated by oestrogen (E 2 ), with LRH-1 mRNA transcript levels higher in oestrogen receptor α (ERα) positive (ER+) breast cancer cells compared to ER− cells. However, the presence of LRH-1 protein in ER− cells suggests discordance between mRNA transcript levels and protein expression. To understand this, we investigated the impact of mRNA and protein stability in determining LRH-1 protein levels in breast cancer cells. LRH-1 transcript levels were significantly higher in ER+ versus ER− breast cancer cells lines; however LRH-1 protein was expressed at similar levels. We found LRH-1 mRNA and protein was more stable in ER− compared to ER+ cell lines. The tumor-specific LRH-1 variant isoform, LRH-1v4, which is highly responsive to E 2 , showed increased mRNA stability in ER− versus ER+ cells. In addition, in MCF-7 and T47-D cell lines, LRH-1 total mRNA stability was reduced with E 2 treatment, this effect mediated by ERα. Our data demonstrates that in ER− cells, increased mRNA and protein stability contribute to the abundant protein expression levels. Expression and immunolocalisation of LRH-1 in ER− cells as well as ER− tumors suggests a possible role in the development of ER− tumors. The modulation of LRH-1 bioactivity may therefore be beneficial as a treatment option in both ER− and ER+ breast cancer

Oestradiol reduces Liver Receptor Homolog-1 mRNA transcript stability in breast cancer cell lines

Energy Technology Data Exchange (ETDEWEB)

Lazarus, Kyren A. [Cancer Drug Discovery Laboratory, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168 (Australia); Environmental and Biotechnology Centre, Swinburne University, Hawthorn, Victoria 3122 (Australia); Zhao, Zhe; Knower, Kevin C. [Cancer Drug Discovery Laboratory, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168 (Australia); To, Sarah Q. [Cancer Drug Discovery Laboratory, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168 (Australia); Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168 (Australia); Chand, Ashwini L. [Cancer Drug Discovery Laboratory, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168 (Australia); Clyne, Colin D., E-mail: Colin.clyne@princehenrys.org [Cancer Drug Discovery Laboratory, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168 (Australia); Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168 (Australia)

2013-08-30

Highlights: •LRH-1 is an orphan nuclear receptor that regulates tumor proliferation. •In breast cancer, high mRNA expression is associated with ER+ status. •In ER−ve cells, despite very low mRNA, we found abundant LRH-1 protein. •Our data show distinctly different LRH-1 protein isoforms in ER− and ER+ breast cancer cells. •This is due to differences in LRH-1 mRNA and protein stability rates. -- Abstract: The expression of orphan nuclear receptor Liver Receptor Homolog-1 (LRH-1) is elevated in breast cancer and promotes proliferation, migration and invasion in vitro. LRH-1 expression is regulated by oestrogen (E{sub 2}), with LRH-1 mRNA transcript levels higher in oestrogen receptor α (ERα) positive (ER+) breast cancer cells compared to ER− cells. However, the presence of LRH-1 protein in ER− cells suggests discordance between mRNA transcript levels and protein expression. To understand this, we investigated the impact of mRNA and protein stability in determining LRH-1 protein levels in breast cancer cells. LRH-1 transcript levels were significantly higher in ER+ versus ER− breast cancer cells lines; however LRH-1 protein was expressed at similar levels. We found LRH-1 mRNA and protein was more stable in ER− compared to ER+ cell lines. The tumor-specific LRH-1 variant isoform, LRH-1v4, which is highly responsive to E{sub 2}, showed increased mRNA stability in ER− versus ER+ cells. In addition, in MCF-7 and T47-D cell lines, LRH-1 total mRNA stability was reduced with E{sub 2} treatment, this effect mediated by ERα. Our data demonstrates that in ER− cells, increased mRNA and protein stability contribute to the abundant protein expression levels. Expression and immunolocalisation of LRH-1 in ER− cells as well as ER− tumors suggests a possible role in the development of ER− tumors. The modulation of LRH-1 bioactivity may therefore be beneficial as a treatment option in both ER− and ER+ breast cancer.

Is breast compression associated with breast cancer detection and other early performance measures in a population-based breast cancer screening program?

Science.gov (United States)

Moshina, Nataliia; Sebuødegård, Sofie; Hofvind, Solveig

2017-06-01

We aimed to investigate early performance measures in a population-based breast cancer screening program stratified by compression force and pressure at the time of mammographic screening examination. Early performance measures included recall rate, rates of screen-detected and interval breast cancers, positive predictive value of recall (PPV), sensitivity, specificity, and histopathologic characteristics of screen-detected and interval breast cancers. Information on 261,641 mammographic examinations from 93,444 subsequently screened women was used for analyses. The study period was 2007-2015. Compression force and pressure were categorized using tertiles as low, medium, or high. χ 2 test, t tests, and test for trend were used to examine differences between early performance measures across categories of compression force and pressure. We applied generalized estimating equations to identify the odds ratios (OR) of screen-detected or interval breast cancer associated with compression force and pressure, adjusting for fibroglandular and/or breast volume and age. The recall rate decreased, while PPV and specificity increased with increasing compression force (p for trend screen-detected cancer, PPV, sensitivity, and specificity decreased with increasing compression pressure (p for trend breast cancer compared with low compression pressure (1.89; 95% CI 1.43-2.48). High compression force and low compression pressure were associated with more favorable early performance measures in the screening program.

Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3

Directory of Open Access Journals (Sweden)

Lund Eiliv

2009-07-01

Full Text Available Abstract Background Gonadotropin releasing hormone (GNRH1 triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3. Methods We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs were genotyped and used to identify haplotype-tagging SNPs (htSNPS in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II, European Prospective Investigation on Cancer and Nutrition (EPIC, Multiethnic Cohort (MEC, Nurses' Health Study (NHS, and Women's Health Study (WHS. Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone were also measured in 4713 study subjects. Results Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Conclusion Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)

International Nuclear Information System (INIS)

Canzian, Federico; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Dossus, Laure; Feigelson, Heather Spencer; Haiman, Christopher A; Hankinson, Susan E; Hoover, Robert; Hunter, David J; Isaacs, Claudine; Kaaks, Rudolf; Lenner, Per; Lund, Eiliv; Overvad, Kim; Palli, Domenico; Pearce, Celeste Leigh; Quiros, Jose R; Riboli, Elio; Stram, Daniel O; Thomas, Gilles; Thun, Michael J; Cox, David G; Trichopoulos, Dimitrios; Gils, Carla H van; Ziegler, Regina G; Henderson, Katherine D; Henderson, Brian E; Berg, Christine; Bingham, Sheila; Boeing, Heiner; Buring, Julie

2009-01-01

Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians

Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

International Nuclear Information System (INIS)

Hsieh, Szu-Min; Smith, Robert A; Lintell, Nicholas A; Hunter, Kent W; Griffiths, Lyn R

2009-01-01

The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A

Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

Directory of Open Access Journals (Sweden)

Lintell Nicholas A

2009-09-01

Full Text Available Abstract Background The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1 underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. Methods The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. Conclusion This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S to Phe (F changes a hydrophilic residue (S to a hydrophobic residue (F and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5

Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

Science.gov (United States)

Tchou, Julia; Zhao, Yangbing; Levine, Bruce L; Zhang, Paul J; Davis, Megan M; Melenhorst, Jan Joseph; Kulikovskaya, Irina; Brennan, Andrea L; Liu, Xiaojun; Lacey, Simon F; Posey, Avery D; Williams, Austin D; So, Alycia; Conejo-Garcia, Jose R; Plesa, Gabriela; Young, Regina M; McGettigan, Shannon; Campbell, Jean; Pierce, Robert H; Matro, Jennifer M; DeMichele, Angela M; Clark, Amy S; Cooper, Laurence J; Schuchter, Lynn M; Vonderheide, Robert H; June, Carl H

2017-12-01

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 7 or 3 × 10 8 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR . ©2017 American Association for Cancer Research.

Is Biological Subtype Prognostic of Locoregional Recurrence Risk in Women With pT1-2N0 Breast Cancer Treated With Mastectomy?

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Truong, Pauline T., E-mail: ptruong@bccancer.bc.ca [Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, BC (Canada); Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, BC (Canada); Sadek, Betro T. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Lesperance, Maria F. [Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, BC (Canada); Alexander, Cheryl S. [Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, BC (Canada); Shenouda, Mina; Raad, Rita Abi; Taghian, Alphonse G. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States)

2014-01-01

Purpose: To examine locoregional and distant recurrence (LRR and DR) in women with pT1-2N0 breast cancer according to approximated subtype and clinicopathologic characteristics. Methods and Materials: Two independent datasets were pooled and analyzed. The study participants were 1994 patients with pT1-2N0M0 breast cancer, treated with mastectomy without radiation therapy. The patients were classified into 1 of 5 subtypes: luminal A (ER+ or PR+/HER 2−/grade 1-2, n=1202); luminal B (ER+ or PR+/HER 2−/grade 3, n=294); luminal HER 2 (ER+ or PR+/HER 2+, n=221); HER 2 (ER−/PR−/HER 2+, n=105) and triple-negative breast cancer (TNBC) (ER−/PR−/HER 2−, n=172). Results: The median follow-up time was 4.3 years. The 5-year Kaplan-Meier (KM) LRR were 1.8% in luminal A, 3.1% in luminal B, 1.7% in luminal HER 2, 1.9% in HER 2, and 1.9% in TNBC cohorts (P=.81). The 5-year KM DR was highest among women with TNBC: 1.8% in luminal A, 5.0% in luminal B, 2.4% in luminal HER 2, 1.1% in HER 2, and 9.6% in TNBC cohorts (P<.001). Among 172 women with TNBC, the 5-year KM LRR were 1.3% with clear margins versus 12.5% with close or positive margins (P=.04). On multivariable analysis, factors that conferred higher LRR risk were tumors >2 cm, lobular histology, and close/positive surgical margins. Conclusions: The 5-year risk of LRR in our pT1-2N0 cohort treated with mastectomy was generally low, with no significant differences observed between approximated subtypes. Among the subtypes, TNBC conferred the highest risk of DR and an elevated risk of LRR in the presence of positive or close margins. Our data suggest that although subtype alone cannot be used as the sole criterion to offer postmastectomy radiation therapy, it may reasonably be considered in conjunction with other clinicopathologic factors including tumor size, histology, and margin status. Larger cohorts and longer follow-up times are needed to define which women with node-negative disease have high postmastectomy LRR

BRCA1 gene expression in relation to prognostic parameters of breast cancer

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Manal Kamal

2011-09-01

Full Text Available The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77% was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases. ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients while the remaining 24 patients (80% showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p < 0.01. The study demonstrated lack of BRCA1 gene expression (mRNA in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

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Blein, Sophie; Bardel, Claire; Danjean, Vincent

2015-01-01

of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected......, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how...... original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects....

MMP-1 expression has an independent prognostic value in breast cancer

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Boström, Pia; Söderström, Mirva; Vahlberg, Tero; Söderström, Karl-Ove; Roberts, Peter J; Carpén, Olli; Hirsimäki, Pirkko

2011-01-01

Breast cancer consists of a variety of tumours, which differ by their morphological features, molecular characteristics and outcome. Well-known prognostic factors, e.g. tumour grade and size, Ki-67, hormone receptor status, HER2 expression, lymph node status and patient age have been traditionally related to prognosis. Although the conventional prognostic markers are reliable in general, better markers to predict the outcome of an individual tumour are needed. Matrix metalloproteinase-1 (MMP-1) expression has been reported to inversely correlate with survival in advanced cancers. In breast cancer MMP-1 is often upregulated, especially in basal-type breast tumours. The purpose of this retrospective study was to analyse MMP-1 expression in breast cancer cells and in cancer associated stromal cells and to correlate the results with traditional prognostic factors including p53 and bcl-2, as well as to patient survival in breast cancer subtypes. Immunohistochemical analysis of MMP-1, ER, PR, Ki-67, HER2, bcl-2, p53 and CK5/6 expression was performed on 125 breast cancers. Statistical analyses were carried out using Kruskal-Wallis and Mann-Whitney -tests. In pairwise comparison Bonferroni-adjustment was applied. Correlations were calculated using Spearman rank-order correlation coefficients. Kaplan-Meier survival analyses were carried out to compare breast cancer-specific survival curves. Factors significantly associated with disease-specific survival in univariate models were included in multivariate stepwise. Positive correlations were found between tumour grade and MMP-1 expression in tumour cells and in stromal cells. P53 positivity significantly correlated with MMP-1 expression in tumour cells, whereas HER2 expression correlated with MMP-1 both in tumour cells and stromal cells. MMP-1 expression in stromal cells showed a significant association with luminal A and luminal B, HER2 overexpressing and triple-negative breast cancer subtypes. The most important finding of

Polymorphic repeat in AIB1 does not alter breast cancer risk

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Haiman, Christopher A; Hankinson, Susan E; Spiegelman, Donna; Colditz, Graham A; Willett, Walter C; Speizer, Frank E; Brown, Myles; Hunter, David J

2000-01-01

We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population. A causal association between endogenous and exogenous estrogens and breast cancer has been established. Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development after binding to their respective steroid hormone receptors. Coactivator and corepressor proteins have recently been identified that interact with steroid hormone receptors and modulate transcriptional activation [1]. AIB1 (amplified in breast 1) is a member of the steroid receptor coactivator (SRC) family that interacts with estrogen receptor (ER)α in a ligand-dependent manner, and increases estrogen-dependent transcription [2]. Amplification and overexpression of AIB1 has been observed in breast and ovarian cancer cell lines and in breast tumors [2,3]. A polymorphic stretch of glutamine amino acids, with unknown biologic function, has recently been described in the carboxyl-terminal region of AIB1 [4]. Among women with germline BRCA1 mutations, significant positive associations were observed between AIB1 alleles with 26 or fewer glutamine repeats and breast cancer risk [5] To establish whether AIB1 repeat alleles are associated with breast cancer risk and specific tumor characteristics among Caucasian women. We evaluated associations prospectively between AIB1 alleles and breast cancer risk in the Nurses' Health Study using a nested case-control design. The Nurses' Health Study was initiated in 1976, when 121 700 US-registered nurses between the ages of 30 and 55 years returned an

Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy

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Truong, Pauline T.; Olivotto, Ivo A.; Kader, Hosam A.; Panades, Miguel; Speers, Caroline H.; Berthelet, Eric

2005-01-01

Purpose: To define the individual factors and combinations of factors associated with increased risk of locoregional recurrence (LRR) that may justify postmastectomy radiotherapy (PMRT) in patients with T1-T2 breast cancer and one to three positive nodes. Methods and Materials: The study cohort comprised 821 women referred to the British Columbia Cancer Agency between 1989 and 1997 with pathologic T1-T2 breast cancer and one to three positive nodes treated with mastectomy without adjuvant RT. The 10-year Kaplan-Meier estimates of isolated LRR and LRR with or without simultaneous distant recurrence (LRR ± SDR) were analyzed according to age, histologic findings, tumor location, size, and grade, lymphovascular invasion status, estrogen receptor (ER) status, margin status, number of positive nodes, number of nodes removed, percentage of positive nodes, and systemic therapy use. Multivariate analyses were performed using Cox proportional hazards modeling. A risk classification model was developed using combinations of the statistically significant factors identified on multivariate analysis. Results: The median follow-up was 7.7 years. Systemic therapy was used in 94% of patients. Overall, the 10-year Kaplan-Meier isolated LRR and LRR ± SDR rate was 12.7% and 15.9%, respectively. Without PMRT, a 10-year LRR risk of >20% was identified in women with one to three positive nodes plus at least one of the following factors: age 25% of nodes positive (all p 25% of nodes positive, medial tumor location, and ER-negative status were statistically significant predictors of isolated LRR and LRR ± SDR. In the classification model, the first split was according to age ( 25% of nodes positive was associated with a risk of LRR ± SDR of 58.0% compared with 23.8% for those with ≤25% of nodes positive (p = 0.01). Of 698 women >45 years, the presence of >25% of nodes positive also conferred a greater LRR ± SDR risk (26.7%) compared with women with ≤25% of nodes positive (10

The role of preoperative systemic treatment in patients with breast cancer

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Sylwia Dębska-Szmich

2016-06-01

Full Text Available The goal of preoperative pharmacotherapy in patients with breast cancer is to enable breast conserving surgery in stage T3N0-1M0 or radical mastectomy in patients with primary inoperative tumors (T1-4N0-3M0. The choice of optimal treatment should be based not only on risk factors resulting from the stage but also on predicted cancer responsiveness to the treatment. The breast cancer subtypes defined by immunohistochemical profile (expression of ER, PR, HER2 and Ki67 are characterized by different responsiveness to therapy. Complete response confirmed by histopathological evaluation after neoadjuvant chemotherapy is a positive prognostic factor in some breast cancer subtypes. This marker is not of value in postmenopausal patients with ER/PR+ HER2– tumors, who are candidates for neoadjuvant hormone therapy. These patients have a good prognosis if in a histopathological report after surgery there are features such as pT1, pN0, Ki67 < 3%, and ER Allred score ≥ 3. The goal of the paper is to present current knowledge about preoperative pharmacotherapy of breast cancer.

Susceptibility to breast cancer and three polymorphisms of GSTZ1.

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Saadat, Iraj; Khalili, Maryam; Nafissi, Samane; Omidvari, Shahpour; Saadat, Mostafa

2012-03-01

Glutathione S-transferases class zeta (GSTζ) is involved in the detoxification of xenobiotic compounds and catalyzes the biotransformation of a variety of α-haloacids including dichloroacetic acid and chlorofluoroacetic acid. It has been reported that, in mice, deficiency of Gstz1 (a member of GSTζ) resulted in the generation of a constant level of oxidative stress. The present study was carried out to investigate the association between genetic polymorphisms of GSTZ1 (in promoter site G-1002A and in coding sites Glu32Lys and Gly42Arg) and risk of breast cancer. We included 106 females with breast cancer and 106 healthy females frequency matched for age. The study polymorphisms were not associated with risk of breast cancer (p>0.05). The polymorphisms of GSTZ1 showed strong linkage disequilibrium among cancer patients and control subjects (p0.05). It seems there is no meaningful relationship between the genetic polymorphisms of GSTZ1 and risk of breast cancer.

Role of KCNMA1 gene in breast cancer invasion and metastasis to brain

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Couraud Pierre-Olivier

2009-07-01

Full Text Available Abstract Background The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BKCa channels in breast cancer metastasis and invasion. Methods We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A, non-metastatic breast cancer (MCF-7, non-brain metastatic breast cancer cells (MDA-MB-231, and brain-specific metastatic breast cancer cells (MDA-MB-361 to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX. Results The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. Conclusion Determining the relative abundance of BKCa channel expression in breast

Role of KCNMA1 gene in breast cancer invasion and metastasis to brain

International Nuclear Information System (INIS)

Khaitan, Divya; Sankpal, Umesh T; Weksler, Babette; Meister, Edward A; Romero, Ignacio A; Couraud, Pierre-Olivier; Ningaraj, Nagendra S

2009-01-01

The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BK Ca ) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BK Ca channels in breast cancer metastasis and invasion. We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BK Ca channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BK Ca channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX). The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BK Ca channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. Determining the relative abundance of BK Ca channel expression in breast cancer metastatic to brain and the mechanism of its

Selected Aspects of Molecular Diagnostics of Constitutional Alterations in BRCA1 and BRCA2 Genes Associated with Increased Risk of Breast Cancer in the Polish Population

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Górski Bohdan

2006-08-01

Full Text Available Abstract Objectives This study was undertaken to determine: 1 Type and prevalence of founder mutations BRCA1 and BRCA2 genes in Polish families with strong aggregation of breast and/or ovarian cancer. 2 Risk of breast and/or ovarian cancer depending on type of BRCA1 gene mutation. 3 Prevalence of BRCA1 mutation and of other alleles presumably linked with predisposition to breast cancer in unselected Polish patients with breast cancer. 4 Risk of breast cancer in patients with 5972C/T polymorphism that alters the BRCA2 protein structure. Summary of the results 1. Among 66 families from several regions in Poland with a strong aggregation of breast/ovarian cancer, founder mutation of the BRCA1 gene were disclosed in 34 families and of the BRCA2 gene in on family. Altogether, seven different mutations were disclosed. Five mutations were found in at least two families in this group. The most frequent mutation was 5382insC (18 families, followed by C61G (7 families and 4153delA (4 families. 2. Among 200 families representative for Poland with strong aggregation of breast/ovarian cancer, mutation of the BRCA1 gene were found in 122 families (61% and of the BRCA2 gene in seven families (3,5%. 119 out of 122 mutations of the BRCA1 gene (97,5% were repeatable. Three recurrent mutations of the BRCA1 gene (5382insC, C61G, 4153delA characteristic for the Polish population were disclosed in 111 families representing 86% of all pathogenic sequences of this gene. 3. The risk of ovarian cancer in carriers of the three most frequent recurrent mutation of the BRCA1 gene in Poland is similar (OR 43.6 for 5382insC and 50 for 4153delA. The risk of breast cancer is significantly different for 4153delA (OR 1 and for other mutations (OR 10.9. 4. Among 2012 unselected breast cancers diagnosed in hospitals of nine Polish cities, mutations of the BRCA1 gene (5382insC, C61G, 4153delA were disclosed in 2.9% patients. CHEK2 alternation (1100delC, IVS2+1G>A, I157T was

Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development.

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Degnim, Amy C; Hoskin, Tanya L; Arshad, Muhammad; Frost, Marlene H; Winham, Stacey J; Brahmbhatt, Rushin A; Pena, Alvaro; Carter, Jodi M; Stallings-Mann, Melody L; Murphy, Linda M; Miller, Erin E; Denison, Lori A; Vachon, Celine M; Knutson, Keith L; Radisky, Derek C; Visscher, Daniel W

2017-07-15

Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm 2 for CD4 + T cells, CD8 + T cells, CD20 + B cells, and CD68 + macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8 + T cells, CD11c + dendritic cells, CD20 + B cells, and CD68 + macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20 + cell density ( P = 0.04). Nearly 42% of BBD cases had no CD20 + B cells in evaluated lobules compared with 28% of BBD controls ( P = 0.02). The absence of CD20 + cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945-52. ©2017 AACR . ©2017 American Association for Cancer Research.

Psychological impact of providing women with personalised 10-year breast cancer risk estimates.

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French, David P; Southworth, Jake; Howell, Anthony; Harvie, Michelle; Stavrinos, Paula; Watterson, Donna; Sampson, Sarah; Evans, D Gareth; Donnelly, Louise S

2018-05-08

The Predicting Risk of Cancer at Screening (PROCAS) study estimated 10-year breast cancer risk for 53,596 women attending NHS Breast Screening Programme. The present study, nested within the PROCAS study, aimed to assess the psychological impact of receiving breast cancer risk estimates, based on: (a) the Tyrer-Cuzick (T-C) algorithm including breast density or (b) T-C including breast density plus single-nucleotide polymorphisms (SNPs), versus (c) comparison women awaiting results. A sample of 2138 women from the PROCAS study was stratified by testing groups: T-C only, T-C(+SNPs) and comparison women; and by 10-year risk estimates received: 'moderate' (5-7.99%), 'average' (2-4.99%) or 'below average' (<1.99%) risk. Postal questionnaires were returned by 765 (36%) women. Overall state anxiety and cancer worry were low, and similar for women in T-C only and T-C(+SNPs) groups. Women in both T-C only and T-C(+SNPs) groups showed lower-state anxiety but slightly higher cancer worry than comparison women awaiting results. Risk information had no consistent effects on intentions to change behaviour. Most women were satisfied with information provided. There was considerable variation in understanding. No major harms of providing women with 10-year breast cancer risk estimates were detected. Research to establish the feasibility of risk-stratified breast screening is warranted.

Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1.

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Xie, Xiayang; Tang, Shou-Ching; Cai, Yafei; Pi, Wenhu; Deng, Libin; Wu, Guangyu; Chavanieu, Alain; Teng, Yong

2016-09-06

Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 (ARF1) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis.

FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

International Nuclear Information System (INIS)

Chen, Yi; Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi; Jing, Qian; Yue, Jiaqi; Liu, Yang; Cheng, Zhong; Li, Jingyi; Song, Haixing; Li, Guoyu; Liu, Rui; Wang, Jinhui

2016-01-01

Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

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Chen, Yi [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Jing, Qian; Yue, Jiaqi; Liu, Yang [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Cheng, Zhong [Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Li, Jingyi, E-mail: li--jingyi@hotmail.com [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Song, Haixing [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Li, Guoyu, E-mail: liguoyulisa@163.com [School of Pharmacy, Shihezi University, Shihezi 832003 (China); Liu, Rui, E-mail: liurui_scu@hotmail.com [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Wang, Jinhui [School of Pharmacy, Shihezi University, Shihezi 832003 (China)

2016-05-20

Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

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Simon N Stacey

2006-07-01

Full Text Available Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014. The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015. Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046 in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors

Induction of Mitochondria Mediated Apoptosis in Human Breast Cancer Cells (T-47D) by Annona reticulata L. Leaves Methanolic Extracts.

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Roham, Pratiksha H; Kharat, Kiran R; Mungde, Priyanka; Jadhav, Mahadev A; Makhija, Surinder J

2016-01-01

Annona reticulata Linn. (Common name: Bullock's-heart) (Annonaceae family) is a semi-evergreen and small deciduous tree. The extracts of various parts of Annona reticulata L. have been reported as cytotoxic to many cancer cells. Annona reticulata L. leaves' methanolic extract (ARME) was prepared and used against the breast cancer cells. The breast cancer cells (T-47D) viability and IC50 were evaluated by Vybrant® MTT Cell Proliferation Assay Kit. Detection of phosphatidylserine on membranes of apoptotic cells was done by Attune flow cytometer. RNA transcripts were quantified in ARME treated and untreated cells. Finally, the Vybrant® FAM Poly Caspases assay kit was used for analysis of polycaspases activity in T-47D cells. The IC50 (5 ± 0.5 µg/mL) of the ARME was found against breast cancer cells (T-47D). The Paclitaxel was used as a control standard drug for the study. The downregulation of Bcl-2 and upregulation of Bax and Bak, and caspases activation suggested induction of apoptosis in T-47D cells by ARME through mitochondrial pathway. The cell cycle halted at G2/M phase in the ARME treated cells. The ARME was found to be effective against Breast cancer cells (T-47D).

AUTOMATED ANALYSIS OF CELL DENSITY IN BREAST CANCER AS AN ADDITIONAL METHOD OF INCREASING OBJECTIVITY AND ACCURACY OF BREAST CANCER PROGNOSIS

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R. M. Paltuev

2017-01-01

Full Text Available Introduction. In the last ten years, it became obvious that on the molecular level breast cancer is a group of heterogenous tumors. The current objective of routine clinical practice of treatment prescription includes accurate disease prognosis for every individual patient and conviction that the risk of breast cancer recurrence after adjuvant hormone therapy without adjuvant chemotherapy doesn’t increase.The study objective is to evaluate how clinical use of risk associated with cell density can in practice improve prognosis of recurrence risk in patients with breast cancer after standard clinical and pathomorphological examinations.Materials and methods. The article analyzes therapy results using data from the cumulative cancer registry of breast cancer diagnosis and treatment of the N.N. Petrov National Medical Research Oncology Center in 2000–2009. The database includes information on diagnosis, treatment, and survival of 5106 patients with breast cancer. Archived material (from 2000 to 2009 from paraffin blocks of the “targeted group” for methods of molecular and genetic profiling was poured into recipient blocks, stained with corresponding antibodies such as widely used ER, PR, HER2/neu, Ki-67 markers as well as poorly studied markers: cell density, р53, CK5/6, CK14, CD4/CD8, p63, EGFR, FOXP3, AR, FOX1.Results. The study of 1118 patients with stage T1–2N0M0 breast cancer has shown that analysis of risk associated with cell density allows to predict disease outcome. Correlation between the marker and the grade of histological malignancy is more rare than for Ki-67 determined in this patient group. As a result, determination of cell density is an additional method to increase objectivity and accuracy of breast cancer prognosis.Conclusions. Automated cell density analysis for breast cancer is almost fully operator-independent which increases accuracy and objectivity of the results. Cell density in breast cancer lower than 3000

Intraindividual variability in reaction time before and after neoadjuvant chemotherapy in women diagnosed with breast cancer.

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Yao, Christie; Rich, Jill B; Tirona, Kattleya; Bernstein, Lori J

2017-12-01

Women treated with chemotherapy for breast cancer experience subtle cognitive deficits. Research has focused on mean performance level, yet recent work suggests that within-person variability in reaction time performance may underlie cognitive symptoms. We examined intraindividual variability (IIV) in women diagnosed with breast cancer and treated with neoadjuvant chemotherapy. Patients (n = 28) were assessed at baseline before chemotherapy (T1), approximately 1 month after chemotherapy but prior to surgery (T2), and after surgery about 9 months post chemotherapy (T3). Healthy women of similar age and education (n = 20) were assessed at comparable time intervals. Using a standardized regression-based approach, we examined changes in mean performance level and IIV (eg, intraindividual standard deviation) on a Stroop task and self-report measures of cognitive function from T1 to T2 and T1 to T3. At T1, women with breast cancer were more variable than controls as task complexity increased. Change scores from T1 to T2 were similar between groups on all Stroop performance measures. From T1 to T3, controls improved more than women with breast cancer. IIV was more sensitive than mean reaction time in capturing group differences. Additional analyses showed increased cognitive symptoms reported by women with breast cancer from T1 to T3. Specifically, change in language symptoms was positively correlated with change in variability. Women with breast cancer declined in attention and inhibitory control relative to pretreatment performance. Future studies should include measures of variability, because they are an important sensitive indicator of change in cognitive function. Copyright © 2016 John Wiley & Sons, Ltd.

TIMP-1 and responsiveness to gemcitabine in advanced breast cancer

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Jørgensen, Charlotte Levin Tykjær; Bjerre, Christina Annette; Ejlertsen, Bent Laursen

2014-01-01

receiving GD. CONCLUSIONS: TIMP-1 status was an independent prognostic factor for OS but not TTP in patients with advanced breast cancer receiving either D or GD. There was no statistically significant interaction between TIMP-1 status and treatment, but a trend towards an incremental OS from the addition...... and predictive marker in advanced breast cancer patients receiving docetaxel (D) or gemcitabine plus docetaxel (GD). METHODS: Patients with locally advanced or metastatic breast cancer who were assigned to D or GD by participation in a randomized phase III trial were included in the study. Assessment of TIMP-1...

Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis.

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Xun Yuan

Full Text Available Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7-11.07 and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS to invasive cancer (OR=3.75; 95% CI, 1.8-7.78. Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43. Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta-analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients.

Symptom burden among young adults with breast or colorectal cancer.

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Sanford, Stacy D; Zhao, Fengmin; Salsman, John M; Chang, Victor T; Wagner, Lynne I; Fisch, Michael J

2014-08-01

Cancer incidence has increased among young adults (YAs) and survival rates have not improved compared with other age groups. Patient-reported outcomes may enhance our understanding of this vulnerable population. In a multisite prospective study, patients completed a cancer symptom inventory at the time of enrollment (T1) and 4 weeks to 5 weeks later (T2). YAs (those aged ≤ 39 years) with breast or colorectal cancer were compared with older adults (those aged ≥ 40 years) with breast or colorectal cancer with regard to symptom severity, symptom interference, changes over time, and medical care. Participants included 1544 patients with breast cancer (96 of whom were YAs) and 718 patients with colorectal cancer (37 of whom were YAs). Compared with older adults, YAs with breast cancer were more likely to report moderate/severe drowsiness, hair loss, and symptom interference with relationships at T1. YAs with colorectal cancer were more likely to report moderate/severe pain, fatigue, nausea, distress, drowsiness, shortness of breath, and rash plus interference in general activity, mood, work, relationships, and life enjoyment compared with older adults. Compared with older adults, shortness of breath, appetite, and sore mouth were more likely to improve in YAs with breast cancer; vomiting was less likely to improve in YAs with colorectal cancer. Referrals for supportive care were few, especially among patients with colorectal cancer. YAs with breast cancer were somewhat more likely to be referred to nutrition and psychiatry services than older patients. YAs reported symptom severity, symptom interference, and variations over time that were distinct from older patients. Distinctions were found to differ by diagnostic group. These findings enhance the understanding of symptom burden in YAs and inform the development of targeted interventions and future research. © 2014 American Cancer Society.

A wide variety of dynamic contrast-enhanced MR appearances of breast cancer: Pathologic correlation study

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Onishi, Masayuki; Furukawa, Akira; Takahashi, Masashi; Murata, Kiyoshi

2008-01-01

Purpose: The aim of this study was to elucidate the characteristic magnetic resonance (MR) appearance of breast cancers, as well as, its variations and to investigate the pathology providing different patterns of dynamic-MR appearances. Materials and methods: Fifty-two women with cancer underwent mastectomy (52 tumors resected) and had MR imaging at our institution between April 2001 and March 2004. MR images of T1WI, T2WI, dynamic-MRI and contrast-enhanced T1WI were obtained and evaluated. Dynamic-MR images were correlated with pathological findings. Results: Common MR appearance of breast cancer was a focal mass either with irregular or spiculated margins with similar signal intensity on T1WI as and similar to higher signal intensity on T2WI compared to the normal mammary gland. On static contrast-enhanced T1WI, apparent enhancement was typically observed. On dynamic MRI, tumor-rim-enhancement on an early phase image and washout enhancement pattern on dynamic images, both characteristic for breast cancer, were observed, however, the prevalence of them was relatively low, which could be explained by the variation of histopathology among breast cancer nodules. Conclusion: In diagnosing breast masses on MRI, as well as the common and characteristic findings of breast cancer, the variations of MR findings and their underlying histopathology should also be considered

Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.

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Cybulski, Cezary; Wokołorczyk, Dominika; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Masojć, Bartłomiej; Deebniak, Tadeusz; Górski, Bohdan; Blecharz, Paweł; Narod, Steven A; Lubiński, Jan

2011-10-01

To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. Seven thousand four hundred ninety-four BRCA1 mutation-negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T). A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected. CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.

PBX1 Genomic Pioneer Function Drives ERα Signaling Underlying Progression in Breast Cancer

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Magnani, Luca; Ballantyne, Elizabeth B.; Zhang, Xiaoyang; Lupien, Mathieu

2011-01-01

Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ERα) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ERα-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ERα in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ERα recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ERα-positive breast cancer patients. These features are markedly different from the previously characterized ERα-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ERα-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ERα-positive breast tumors, as it guides ERα genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression. PMID:22125492

Human breast cancer; in vivo and in vitro H MR spectroscopy

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Chung, Tae Woong; Kang, Heoung Keun; Jeong, Gwang Woo; Park, Jin Gyoon; Seo, Jeong Jin; Lee, Jung Hee [Ulsan Univ. College of Medicine, Seoul (Korea, Republic of)

2001-02-01

The purpose of this study was to determione, using in vivo and in vitro H MRS (MR spectroscopy), the characteristic biochemical metabolites related with breast cancer, and to assess the clinical usefulness and limitations of this modality. For in vivo H MRS, nine patients with breast cancer and two normal volunteers were examined on a 1.5T MR imager equipped with facilities for spectroscopy. In order to localize the breast lesion, axial and sagittal T1-weighted images and fat-suppressed T2-weighted images were obtained just prior to MRS: MR spectra were acquired at TR=3000 msec and TE=144 msec. For in vitro H MRS, breast tumor and adjacent normal tissue were extracted from 13 patients with breast cancer, and in two of these, both in vivo and in vitro H MRS were performed. All in vitro H MRS specimens were immediately immersed in liquid nitrogen, and then in a preparation of perchloric acid. For quantitative analysis of the MR spectra of cancerous and normal breast tissue, the paired t-test was used (p<0.05). At H MRS in vivo, choline and two lipids were identified at 3.21 ppm and 0.9ppm, respectively. The distinction between cancerous and normal breast tissue was based on the higher level of choline (3.21 ppm) present in the former. At H MRS in vitro, on the other hand, mean and standard deviation (% standard deviation) for the various metabolites in cancerous and normal breast tissue were as follows; choline, 30.195 2.448(8.108) and 22.648 1.938(8.556): trimethylamine, diagnosis of breast cancer. resolution, may be very useful0.335(9.769) and 0.640 0.099(15.394): lactate, 16.388 1.134(6.922) and 9.715 0.385(3.965): inositol, 1.970 0.282(14.334) and 3.859 0.502(13.020): and taurine, 6.614 0.556(8.412) and 10.748 1.206(11.222). High levels of choline (p=0.026), trimethylamine (p=0.001), sarcosine (p=0.009), and lactate (p=0.009), and lower levels of inositol(p=0.006) and taurine (p=0.008) were characteristic findings in cancerous as compared with normal breast

Life course evolution of body size and breast cancer survival in the E3N cohort.

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His, Mathilde; Le Guélennec, Marine; Mesrine, Sylvie; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Françoise; Fagherazzi, Guy; Dossus, Laure

2018-04-15

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty and early adulthood and body size trajectories from childhood to adulthood. Self-assessed body size at age 8, at puberty, at age 20-25 and at age 35-40 and trajectories of body size of 4,662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models. Four trajectories of body size were identified (T1 "moderate increase," T2 "stable/low increase," T3 "increase at puberty" and T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 vs. T2 = 1.27; 95% CI = 1.01-1.60) and an increased risk of second invasive cancer event (HR T1 vs. T2 = 1.25; 95% CI = 1.06-1.47). Silhouettes at various ages were not associated with survival. Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. © 2017 UICC.

Association of two mutations in the CHEK2 gene with breast cancer

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Bogdanova, N.; Enben-Dubrowinskaja, N.; Doerk, T.; Feshchenko, S.; Lazyuk, G.I.; Rogov, Yu.I.

2005-01-01

Cell-cycle checkpoint kinase 2 (CHEK2) is a central mediator of cellular responses to DNA damage. Ionizing radiation activates the CHEK2 protein via ATM-mediated phosphorylation and activated CHEK2 kinase can phosphorylate several substrates, including Cdc25A, p53 and E2F1, which mediate cell cycle arrest and apoptosis. CHEK2 phosphorylation of the breast cancer susceptibility protein BRCA1 regulates DNA double-strand break repair, and deletion of CHEK2 potentiate the incidence of mammary carcinomas in BRCA1 conditional mutant mice. A truncating variant of CHEK2, the 1100 delC mutation, has been identified as a low-penetrance breast-cancer susceptibility allele. Heterozygous 1100 delC carriers have an approximately 2-fold increased risk for breast cancer. The role of variants in CHEK2 other than 1100 delC is less clear. To assess the role of these CHEK2 variants in breast cancer, we conducted an association study of the I157T and IVS211G>A mutations in breast cancer case-control settings from the Belarus populations. Our series consisted of 424 breast cancer patients and 307 population controls. The missense substitution I157T was identified in 24/424 cases (5.7%) vs. 4/307 controls (1.3%; OR 54.5, 95% CI 1.6-13.2, p 5 0.005) in investigated cohorts. The splicing mutation IVS211G > A was infrequent, being observed 4/424 patients (0.9%). Heterozygous CHEK2 mutation carriers tended to be diagnosed at an earlier age, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and non carriers. Our data indicate that the I157T allele, and possibly the IVS211G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility. (authors)

EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

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Naiara Perurena

2017-01-01

Full Text Available Abstract Background Activated protein C/endothelial protein C receptor (APC/EPCR axis is physiologically involved in anticoagulant and cytoprotective activities in endothelial cells. Emerging evidence indicates that EPCR also plays a role in breast stemness and human tumorigenesis. Yet, its contribution to breast cancer progression and metastasis has not been elucidated. Methods Transcriptomic status of EPCR was examined in a cohort of 286 breast cancer patients. Cell growth kinetics was evaluated in control and EPCR and SPARC/osteonectin, Cwcv, and kazal-like domains proteoglycan (SPOCK1/testican 1 silenced breast cancer cells in 2D, 3D, and in co-culture conditions. Orthotopic tumor growth and lung and osseous metastases were evaluated in several human and murine xenograft breast cancer models. Tumor-stroma interactions were further studied in vivo by immunohistochemistry and flow cytometry. An EPCR-induced gene signature was identified by microarray analysis. Results Analysis of a cohort of breast cancer patients revealed an association of high EPCR levels with adverse clinical outcome. Interestingly, EPCR knockdown did not affect cell growth kinetics in 2D but significantly reduced cell growth in 3D cultures. Using several human and murine xenograft breast cancer models, we showed that EPCR silencing reduced primary tumor growth and secondary outgrowths at metastatic sites, including the skeleton and the lungs. Interestingly, these effects were independent of APC ligand stimulation in vitro and in vivo. Transcriptomic analysis of EPCR-silenced tumors unveiled an effect mediated by matricellular secreted proteoglycan SPOCK1/testican 1. Interestingly, SPOCK1 silencing suppressed in vitro 3D growth. Moreover, SPOCK1 ablation severely decreased orthotopic tumor growth and reduced bone metastatic osteolytic tumors. High SPOCK1 levels were also associated with poor clinical outcome in a subset breast cancer patients. Our results suggest that EPCR

Challenging metastatic breast cancer with the natural defensin PvD1.

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Figueira, Tiago N; Oliveira, Filipa D; Almeida, Inês; Mello, Érica O; Gomes, Valdirene M; Castanho, Miguel A R B; Gaspar, Diana

2017-11-09

Metastatic breast cancer is a very serious life threatening condition that poses many challenges for the pharmaceutical development of effective chemotherapeutics. As the therapeutics targeted to the localized masses in breast improve, metastatic lesions in the brain slowly increase in their incidence compromising successful treatment outcomes overall. The blood-brain-barrier (BBB) is one important obstacle for the management of breast cancer brain metastases. New therapeutic approaches are in demand for overcoming the BBB's breaching by breast tumor cells. In this work we demonstrate the potential dual role of a natural antimicrobial plant defensin, PvD 1 : it interferes with the formation of solid tumors in the breast and concomitantly controls adhesion of breast cancer cells to human brain endothelial cells. We have used a combination of techniques that probe PvD 1 's effect at the single cell level and reveal that this peptide can effectively damage breast tumor cells, leaving healthy breast and brain cells unaffected. Results suggest that PvD1 quickly internalizes in cancer cells but remains located in the membrane of normal cells with no significant damage to its structure and biomechanical properties. These interactions in turn modulate cell adhesiveness between tumor and BBB cells. PvD 1 is a potential template for the design of innovative pharmacological approaches for metastatic breast cancer treatment: the manipulation of the biomechanical properties of tumor cells that ultimately prevent their attachment to the BBB.

PPARgamma-PGC-1alpha activity is determinant of alcohol related breast cancer

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Koefoed Petersen, Rasmus; Benzon Larsen, Signe; Jensen, Ditte Marie

2012-01-01

Alcohol is a risk factor for postmenopausal breast cancer. One of several proposed mechanisms is that alcohol-related breast cancer is caused by increased sex hormone levels. PPARγ inhibits aromatase transcription in breast adipocytes. We reproduced previously found allele-specific effects...... of the wildtype Pro-allele of PPARG Pro12Ala in alcohol related breast cancer. In transiently transfected cells, transcriptional activation by PPARγ and the PPARγ-PGC-1α complex was inhibited by ethanol. PPARγ 12Ala-mediated transcription activation was not enhanced by PGC-1α, resulting in allele......-specific transcription activation by the PPARγ 12Pro-PGC-1α complex. Our results suggest that PPARγ and PGC-1α activity is an important determinant of alcohol related breast cancer....

Evaluation of Cytotoxicity Effects of Oleo-Gum-Resin and Its Essential Oil of Ferula assa-foetida and Ferulic Acid on 4T1 Breast Cancer Cells.

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Bagheri, Seyyed Majid; Asl, Amir Abdian; Shams, Ali; Mirghanizadeh-Bafghi, Seyyed Ali; Hafizibarjin, Zeynab

2017-01-01

Cancer causes significant morbidity and mortality and is a major public health problem worldwide. Breast cancer is a leading cause of cancer-associated mortality in women, and the incidence is also on the rise in the entire world. Medicinal plants have been an important source of several clinically useful anticancer agents. In this study, we studied the growth inhibitory effect of asafoetida and its essential oil and ferulic acid on antitumor activity using mouse breast cancer cell line. For this aim, cells were exposed to these components at different concentrations and for different time durations. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to characterize the cytotoxicity of the constituents used. Our results showed that all three constituents could inhibit 4T1 cell proliferation. Our MTT assay results showed a significant cytotoxicity effect in a time- and concentration-dependent manner. It also demonstrated that essential oil of asafoetida has a stronger effect in decreasing viability breast cancer cells. Ferulic acid showed a significant effect only at a dose of 500 μg/ml. Based on the results of cellular carried out in this study, we could demonstrate that asafoetida and its essential oil and ferulic acid have inhibitory effect on the growth of breast cancer cell line. As evidenced from these preliminary results, asafoetida and its derivative constituents may be considered as attractive alternatives to serve as lead compounds in drug development for breast cancer as an adjuvant therapy. However, much remains to be done before such agent could be introduced to the clinic.

High resolution MRI of the breast at 3 T: which BI-RADS {sup registered} descriptors are most strongly associated with the diagnosis of breast cancer?

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Pinker-Domenig, K.; Helbich, T.H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Bogner, W.; Gruber, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Bickel, H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Duffy, S. [Queen Mary University of London, Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London (United Kingdom); Schernthaner, M. [Medical University Vienna, Dept. of Radiology, Vienna (Austria); Dubsky, P. [Medical University Vienna, Dept. of Surgery, Vienna (Austria); Pluschnig, U. [Medical University Vienna, Dept. of Internal Medicine, Division of Oncology, Vienna (Austria); Rudas, M. [Medical University Vienna, Clinical Institute of Pathology, Vienna (Austria); Trattnig, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria)

2012-02-15

To identify which breast lesion descriptors in the ACR BI-RADS registered MRI lexicon are most strongly associated with the diagnosis of breast cancer when performing breast MR imaging at 3 T. 150 patients underwent breast MR imaging at 3 T. Lesion size, morphology and enhancement kinetics were assessed according to the BI-RADS {sup registered} classification. Sensitivity, specificity and diagnostic accuracy were assessed. The effects of the BI-RADS {sup registered} descriptors on sensitivity and specificity were evaluated. Data were analysed using logistic regression. Histopathological diagnoses were used as the standard of reference. The sensitivity, specificity and diagnostic accuracy of breast MRI at 3 T was 99%, 81% and 93%, respectively. In univariate analysis, the final diagnosis of malignancy was positively associated with irregular shape (p < 0.001), irregular margin (p < 0.001), heterogeneous enhancement (p < 0.001), Type 3 enhancement kinetics (p = 0.02), increasing patient age (p = 0.02) and larger lesion size (p < 0.001). In multivariate analysis, significant associations with malignancy remained for mass shape (p = 0.06), mass margin (p < 0.001), internal enhancement pattern (p = 0.03) and Type 3 enhancement kinetics (p = 0.06). The ACR BI-RADS {sup registered} breast lesion descriptors that are mostly strongly associated with breast cancer in breast MR imaging at 3 T are lesion shape, lesion margin, internal enhancement pattern and Type 3 enhancement kinetics. (orig.)

[The therapeutic effect of HSV1-hGM-CSF combined with doxorubicin on the mouse breast cancer model].

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Zhuang, X F; Zhang, S R; Liu, B L; Wu, J L; Li, X Q; Gu, H G; Shu, Y

2018-03-23

Objective: To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice. Methods: We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed. Results: Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro . Doxorubicin induced the G(2)/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm(3,) (216.80±57.18)mm(3,) (246.10±21.90)mm(3,) (327.50±44.24)mm(3,) (213.30±32.31)mm(3) and (495.80±75.87)mm(3) in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo ( P CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control ( P CSF is observed in 4T1 mouse breast cancer.

Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.

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Molanouri Shamsi, M; Chekachak, S; Soudi, S; Quinn, L S; Ranjbar, K; Chenari, J; Yazdi, M H; Mahdavi, M

2017-02-01

Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

Science.gov (United States)

Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

2018-01-01

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

The cytotoxic effect of Elephantopus scaber Linn extract against breast cancer (T47D) cells

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Sulistyani, N.; Nurkhasanah

2017-11-01

Breast cancer is one of the main cause of death. Elephantopus scaber Linn (ES) which has been used as a traditional medicine contains an antitumor compounds. This study aimed to explore the active fraction from ethanolic extract of ES as anticancer and to determine its inhibition effect on the cell proliferation cycle of breast cancer (T47D) cells. The ES leaf was macerated with ethanol and then evaporated to get the concentrated extract. The extract was fractionated using petroleum ether, chloroform, and methanol respectively. The cytotoxic activity of each fraction was carried out with MTT method, and the inhibition of cell cycle test were observed by flowcytometry method. The result showed that ES and the fractions have cytotoxic activity against T47D cell lines with IC50 values of extract, petroleum ether, chloroform, and methanol fractions were 58.36±2.38, 132.17±9.69, 7.08±2.11, and 572.89±69.23 µg/mL. The inhibition effect of ethanol extract on the lifecycle of cells was occured in sub G1 phase. There was no prolonging of G1, S, G2/M and polyploidy phase of T47D cell lines. The chloroform fraction of ES is the most cytotoxic fraction against T47D cells without prolonging the cell lifecycle.

Prognostic value of human apurinic/apyrimidinic endonuclease 1 (APE1 expression in breast cancer.

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Joohyun Woo

Full Text Available Human apurinic/apyrimidinic endonuclease 1 (APE1 is an essential protein for DNA base excision repair (BER and redox regulation. The ability of cancer cells to recognize DNA damage and initiate DNA repair is an important mechanism for therapeutic resistance. Several recent studies have suggested that APE1 expression levels and/or subcellular dysregulation may be used to indicate the sensitivity of tumors to radiotherapy or chemotherapy. In this study, we assessed the prognostic significance of APE1 and differences in APE1 expression levels according to breast cancer molecular subtypes. We analyzed formalin-fixed, paraffin-embedded tumor tissue sections from 243 cases diagnosed as invasive breast cancer at Ewha Womans University Medical Center between January 2003 and December 2008. Immunohistochemistry was performed and the nuclear level of APE1 was scored by taking into account the percentage of positive cells. Medical records were reviewed to investigate clinicopathologic characteristics. We found that nuclear APE1 high-level expression (proportion ≥50% in breast cancer showed a tendency towards unfavorable prognosis regarding disease-free survival (p = 0.093. However, there was no significant difference in overall survival between low and high-level expression groups (p = 0.294. Interestingly, within the Ki-67 low-level expression group, APE1 low-level expression was significantly associated with poor overall survival (p = 0.007. A significant positive correlation was observed between APE1 nuclear expression and estrogen receptor status (75.7% vs. 59.7%, p = 0.022. Also, the luminal A subtype was the most commonly observed breast cancer subtype in the APE1 high-level expression group (61.6% vs. 45.2%, p = 0.000. This study suggests that APE1 expression may be associated with breast cancer prognosis. In particular, its role as a prognostic factor would be significant for breast cancers with a low Ki-67 proliferation index

Increased STAT1 signaling in endocrine-resistant breast cancer.

Directory of Open Access Journals (Sweden)

Rui Huang

Full Text Available Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1 and fully resistant (MCF-7/LCC9 variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701 and phospho-STAT3(Ser727 were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold, phospho-STAT3(Ser727 (∼1.8 fold, and STAT5 (∼1.5 fold and nuclear phospho-STAT3(Ser727 (∼1.5 fold in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532. When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067, while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001. Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006. These results suggest

Benign breast disease, mammographic breast density, and the risk of breast cancer.

Science.gov (United States)

Tice, Jeffrey A; O'Meara, Ellen S; Weaver, Donald L; Vachon, Celine; Ballard-Barbash, Rachel; Kerlikowske, Karla

2013-07-17

Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.

Sensitivity of breast cancer cell lines to recombinant thiaminase I.

Science.gov (United States)

Liu, Shuqian; Monks, Noel R; Hanes, Jeremiah W; Begley, Tadhg P; Yu, Hui; Moscow, Jeffrey A

2010-05-01

We have previously shown that the expression of the thiamine transporter THTR2 is decreased sevenfold in breast cancer, which may leave breast cancer cells vulnerable to acute thiamine starvation. This concept was supported by the observation that MDA231 breast cancer xenografts demonstrated growth inhibition in mice fed a thiamine-free diet. We purified recombinant Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, to study acute thiamine starvation in breast cancer. Thiaminase I enzyme was cytotoxic in six breast cancer cell lines with IC(50)s ranging from 0.012 to 0.022 U/ml. The growth inhibitory effects of the combination of thiaminase I with either doxorubicin or paclitaxel were also examined. Over a wide range of drug concentrations, thiaminase 1 was consistently synergistic or additive with doxorubicin and paclitaxel in MCF-7, ZR75, HS578T and T47D cell lines, with most combinations having a calculated combination index (CI) of less than 0.8, indicating synergy. Although thiaminase I exposure did not stimulate the energy-sensing signaling kinases AKT, AMPK and GSK-3beta in MCF-7, ZR75, HS578T and T47D cell lines, thiaminase I exposure did stimulate expression of the ER stress response protein GRP78. In summary, thiaminase I is cytotoxic in breast cancer cell lines and triggers the unfolded protein response. These findings suggest that THTR2 down-regulation in breast tumors may present a nutritional vulnerability that could be exploited by thiaminase I enzyme therapy.

A randomized trial of tamoxifen with or without breast radiation in women over 50 years of age with T1/2 N0 disease

International Nuclear Information System (INIS)

Fyles, A.; Manchul, L.; McCready, D.; Merante, P.; Pintilie, M.; Trudeuau, M.; Olivotto, I.; Weir, L.

2003-01-01

To determine the effect of breast radiation (RT) on disease-free survival (DFS) and ipsilateral breast relapse (IBR) in women over 50 with T1 and T2 node negative breast cancer. Between December 1992 and June 2000, 769 women were randomized to RT and Tamoxifen (Tam) 20 mg daily for 5 years or Tam alone. Median age was 68 years, 639 patients had pT1 lesions and ER/PR were positive in 700 patients. Six hundred and thirty-four patients had pathologically negative nodes and 135 over age 65 were clinically node negative. Median follow-up was 5.6 years and patient and tumour characteristics were well balanced between the two arms. Overall, there were 54 relapses from breast cancer in the Tam arm and 27 in the Tam + RT arm. IBR at 5 years was 7.7% in the Tam arm compared to 0.6% in the Tam + RT group (p<0.0001). Significant factors for breast relapse and DFS at 5 years included tumour size (p=0.02 and 0.0001 respectively), hormone-receptor status (p=0.0008 and 0.0001), grade (p=0.001 and 0.003) and treatment arm (p=0.0001 and 0.004). Four-hundred and nineteen patients with low-risk features (T1, receptor-positive and grade 1/2) treated with Tam alone had a 5% risk of IBR at 5 years, increasing to 10% at 8 years. There was no difference in relapse at regional or distant sites, or in the contralateral breast. No difference was seen in the number of deaths due to breast cancer (13 and 11 for Tam + RT and Tam, respectively), nor in OS (93% at 5 years in both arms). Tamoxifen and breast RT results in a significantly lower rate of breast relapse than Tam alone in women over 50 with node-negative breast cancer. There does not appear to be a low-risk group who can be treated with Tamoxifen without breast radiation

Association of Genetic Susceptibility Variants for Type 2 Diabetes with Breast Cancer Risk in Women of European Ancestry

Science.gov (United States)

Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K.; Milne, Roger L.; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E.; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V.; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G.; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jasmine, Farzana; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A.; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E.; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C.; Swerdlow, Anthony J; Toland, Amanda E.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B.; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S.; Winqvist, Robert; Zamora, M. Pilar; Zhao, Hui; Dunning, Alison M.; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F.; Zheng, Wei

2016-01-01

Purpose Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at P < 0.001), rs9939609 (FTO) (OR = 0.94, 95% CI = 0.92 – 0.95, P = 4.13E-13), rs7903146 (TCF7L2) (OR = 1.04, 95% CI = 1.02 – 1.06, P = 1.26E-05), and rs8042680 (PRC1) (OR = 0.97, 95% CI = 0.95 – 0.99, P = 8.05E-04). Conclusions We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk. PMID:27053251

Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1–AKT interaction

International Nuclear Information System (INIS)

Fang, Xian-Ying; Chen, Wei; Fan, Jun-Ting; Song, Ran; Wang, Lu; Gu, Yan-Hong; Zeng, Guang-Zhi; Shen, Yan; Wu, Xue-Feng; Tan, Ning-Hua; Xu, Qiang; Sun, Yang

2013-01-01

In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore, RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT. - Highlights: ► Plant cyclopeptide RA-V kills human breast cancer cells. ► RA-V triggered mitochondrial apoptotic pathway in human breast cancer cells. ► RA-V inhibited phosphorylation of AKT and PDK1 in breast cancer MCF-7 cells. ► Its mechanism is related to the blockage of the interaction between PDK1 and AKT

Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1–AKT interaction

Energy Technology Data Exchange (ETDEWEB)

Fang, Xian-Ying; Chen, Wei [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing (China); Fan, Jun-Ting [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China); Song, Ran; Wang, Lu [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing (China); Gu, Yan-Hong [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zeng, Guang-Zhi [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China); Shen, Yan; Wu, Xue-Feng [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing (China); Tan, Ning-Hua, E-mail: nhtan@mail.kib.ac.cn [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing (China); Sun, Yang, E-mail: yangsun@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing (China)

2013-02-15

In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore, RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT. - Highlights: ► Plant cyclopeptide RA-V kills human breast cancer cells. ► RA-V triggered mitochondrial apoptotic pathway in human breast cancer cells. ► RA-V inhibited phosphorylation of AKT and PDK1 in breast cancer MCF-7 cells. ► Its mechanism is related to the blockage of the interaction between PDK1 and AKT.

Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in Breast Cancer after Immunotherapy.

Science.gov (United States)

Page, David B; Yuan, Jianda; Redmond, David; Wen, Y Hanna; Durack, Jeremy C; Emerson, Ryan; Solomon, Stephen; Dong, Zhiwan; Wong, Phillip; Comstock, Christopher; Diab, Adi; Sung, Janice; Maybody, Majid; Morris, Elizabeth; Brogi, Edi; Morrow, Monica; Sacchini, Virgilio; Elemento, Olivier; Robins, Harlan; Patil, Sujata; Allison, James P; Wolchok, Jedd D; Hudis, Clifford; Norton, Larry; McArthur, Heather L

2016-10-01

In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 10 6 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835-44. ©2016 AACR. ©2016 American Association for Cancer Research.

Clinical studies on gastric cancer and breast cancer among A-bomb survivors

Energy Technology Data Exchange (ETDEWEB)

Yamagata, S; Ohya, M; Nagusa, Y; Harada, T; Tani, T [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

1977-04-01

Fifty-five cases of gastric cancer and 14 cases of breast cancer among A-Bomb survivors, which had been treated at Dept. of Surgery, Research Institute for Nuclear Medicine and Biology of Hiroshima Univ., were discussed. Both gastric cancer and breast cancer were recognized more in A-Bomb survivors of advanced age. Particularly, the number of gastric cancer in A-Bomb survivors of over 65-year old was about double the number of unexposed persons. Ratio of male to female in A-Bomb survivors with gastric cancer was 1.6:1, and the ratio of female was higher as compared to the ratio in unexposed persons (2.6:1). Gastric cancer of stage III and IV in A-Bomb survivors was 54.5%, and advanced cancer was comparatively few in A-Bomb survivors as compared to in unexposed persons (78.2%). Similarly, comparatively early stage breast cancer of stage I and II was recognized more in A-Bomb survivors. Particularly, T/sub 1/ and T/sub 2/ in which tumor was small in size showed very high percentage of 92.9% in A-Bomb survivors. In gastric cancer in A-Bomb survivors, poorly differentiated adenocarcinoma showed the highest percentage of 34.5%. However, there was no significant difference according to the exposure conditions. As to histological type of breast cancer, medullary tubular adenocarcinoma abounds mostly in both A-Bomb survivors (71.4%) and unexposed persons (75.9%). As the influence of operation, anemia was recognized before operation strongly in A-Bomb survivors with gastric cancer of over 65-year old. After the operation, transient rise of GOT and GPT was recognized in A-Bomb survivors of advanced age with gastric cancer. However, there was no difference in postoperative complications between A-Bomb survivors and unexposed persons.

Breast cancer

International Nuclear Information System (INIS)

Tokunaga, Masayoshi

1992-01-01

More than 20-year follow-up of A-bomb survivors in Hiroshima and Nagasaki has a crucial role in determining the relationship of radiation to the occurrence of breast cancer. In 1967, Wanebo et al have first reported 27 cases of breast cancer during the period 1950-1966 among the Adult Health Study population of A-bomb survivors. Since then, follow-up surveys for breast cancer have been made using the Life Span Study (LSS) cohort, and the incidence of breast cancer has increased year by year; that is breast cancer was identified in 231 cases by the first LSS series (1950-1969), 360 cases by the second LSS series (1950-1974), 564 cases by the third LSS series (1950-1980), and 816 cases in the fourth LSS series (1950-1085). The third LSS series have revealed a high risk for radiation-induced breast cancer in women aged 10 or less at the time of exposure (ATE). Both relative and absolute risks are found to be decreased with increasing ages ATE. Based on the above-mentioned findings and other studies on persons exposed medical radiation, radiation-induced breast cancer is characterized by the following: (1) the incidence of breast cancer is linearly increased with increasing radiation doses; (2) both relative and absolute risks for breast cancer are high in younger persons ATE; (3) age distribution of breast cancer in proximally exposed A-bomb survivors is the same as that in both distally A-bomb survivors and non-exposed persons, and there is no difference in histology between the former and latter groups. Thus, immature mammary gland cells before the age of puberty are found to be most radiosensitive. (N.K.)

Checkpoint Kinase 1 Expression Predicts Poor Prognosis in Nigerian Breast Cancer Patients.

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Ebili, Henry Okuchukwu; Iyawe, Victoria O; Adeleke, Kikelomo Rachel; Salami, Babatunde Abayomi; Banjo, Adekunbiola Aina; Nolan, Chris; Rakha, Emad; Ellis, Ian; Green, Andrew; Agboola, Ayodeji Olayinka Johnson

2018-02-01

Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population. We therefore aimed to investigate the clinicopathological, biological, and prognostic significance of CHEK1 expression in a cohort of Nigerian breast cancer cases. Tissue microarrays of 207 Nigerian breast cancer cases were tested for CHEK1 expression using immunohistochemistry. The clinicopathological, molecular, and prognostic characteristics of CHEK1-positive tumours were determined using the Chi-squared test and Kaplan-Meier and Cox regression analyses in SPSS Version 16. Nuclear expression of CHEK1 was present in 61% of breast tumours and was associated with tumour size, triple-negative cancer, basal-like phenotype, the epithelial-mesenchymal transition, p53 over-expression, DNA homologous repair pathway dysfunction, and poor prognosis. The rate expression of CHEK1 is high in Nigerian breast cancer cases and is associated with an aggressive phenotype and poor prognosis.

Analysis of BRCA1 involvement in breast cancer in Indian women

Indian Academy of Sciences (India)

The involvement of the familial breast-ovarian cancer gene (BRCA1) in the molecular pathogenesis of breast cancer among Indian women is unknown. We have used a set of microsatellite polymorphisms to examine the frequency of allele loss at the BRCA1 region on chromosome 17q21, in a panel of 80 human breast ...

Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women

Science.gov (United States)

2010-01-01

Introduction The potential association between hypo- and hyperthyroid disorders and breast cancer has been investigated in a large number of studies during the last decades without conclusive results. This prospective cohort study investigated prediagnostic levels of thyrotropin (TSH) and triiodothyronine (T3) in relation to breast cancer incidence in pre- and postmenopausal women. Methods In the Malmö Preventive Project, 2,696 women had T3 and/or TSH levels measured at baseline. During a mean follow-up of 19.3 years, 173 incident breast cancer cases were retrieved using record linkage with The Swedish Cancer Registry. Quartile cut-points for T3 and TSH were based on the distribution among all women in the study cohort. A Cox's proportional hazards analysis was used to estimate relative risks (RR), with a confidence interval (CI) of 95%. Trends over quartiles of T3 and TSH were calculated considering a P-value < 0.05 as statistically significant. All analyses were repeated for pre- and peri/postmenopausal women separately. Results Overall there was a statistically significant association between T3 and breast cancer risk, the adjusted RR in the fourth quartile, as compared to the first, was 1.87 (1.12 to 3.14). In postmenopausal women the RRs for the second, third and fourth quartiles, as compared to the first, were 3.26 (0.96 to 11.1), 5.53 (1.65 to 18.6) and 6.87 (2.09 to 22.6), (P-trend: < 0.001). There were no such associations in pre-menopausal women, and no statistically significant interaction between T3 and menopausal status. Also, no statistically significant association was seen between serum TSH and breast cancer. Conclusions This is the first prospective study on T3 levels in relation to breast cancer risk. T3 levels in postmenopausal women were positively associated with the risk of breast cancer in a dose-response manner. PMID:20540734

VEGFA GENE POLYMORPHISM (С-2578A, C+936T IN PATIENTS WITH BREAST CANCER

Directory of Open Access Journals (Sweden)

A. V. Shevchenko

2012-01-01

Full Text Available Abstract. Angiogenesis plays the major role in growth, progression and metastasis of different solid umors. Vascular endothelium growth factor (VEGF is a basic factor of angiogenesis regulation. The aim of present study was to evaluate possible correlations between C-2578A and C+936T VEGFА gene functional polymorphisms, and risk of breast cancer development. An association of -2578AA and -2578СС /+936СС VEGFA polymorphisms with incidence of breast cancer was revealed in our study. Distinct features of VEGFA genotype distribution were found for women with lymphogenic metastases and differences in menstrual status.

Breast MRI increases the number of mastectomies for ductal cancers, but decreases them for lobular cancers

NARCIS (Netherlands)

Lobbes, Marc B.I.; Vriens, Ingeborg J.H.; van Bommel, Annelotte C.M.; Nieuwenhuijzen, Grard A.P.; Smidt, Marjolein L.; Boersma, Liesbeth J.; van Dalen, Thijs; Smorenburg, Carolien; Struikmans, Henk; Siesling, Sabine; Voogd, Adri C.; Tjan-Heijnen, Vivianne C.G.

2017-01-01

Purpose In this retrospective population-based cohort study, we analyzed breast MRI use and its impact on type of surgery, surgical margin involvement, and the diagnosis of contralateral breast cancer. Methods All Dutch patients with cT1–4N0–3M0 breast cancer diagnosed in 2011–2013 and treated with

Proportional incidence and radiological review of large (T2+) breast cancers as surrogate indicators of screening programme performance

International Nuclear Information System (INIS)

Ciatto, S.; Bernardi, D.; Pellegrini, M.; Borsato, G.; Peterlongo, P.; Gentilini, M.A.; Caumo, F.; Frigerio, A.; Houssami, N.

2012-01-01

Surrogate measures of screening performance [e.g. interval cancer (IC) proportional incidence] allow timely monitoring of sensitivity and quality. This study explored measures using large (T2+) breast cancers as potential indicators of screening performance. The proportional incidence of T2+ cancers (observed/expected cases) in a population-based screening programme (Trento, 2001-2009) was estimated. A parallel review of 'negative' preceding mammograms for screen-detected T2+ and for all ICs, using 'blinded' independent readings and case-mixes (54 T2+, 50 ICs, 170 controls) was also performed. T2+ cancers were observed in 168 screening participants: 48 at first screen, 67 at repeat screening and 53 ICs. The T2+ estimated proportional incidence was 68% (observed/expected = 168/247), corresponding to an estimated 32% reduction in the rate of T2+ cancers in screening participants relative to that expected without screening. Majority review classified 27.8% (15/54) of T2+ and 28% (14/50) of ICs as screening error (P = 0.84), with variable recall rates amongst radiologists (8.8-15.2%). T2+ review could be integrated as part of quality monitoring and potentially prove more feasible than IC review for some screening services. circle Interval breast cancers, assumed as screening failures, are monitored to estimate screening performance circle Large (T2+) cancers at screening may also represent failed prior screening detection circle Analysis of T2+ lesions may be more feasible than assessing interval cancers circle Analysis of T2+ cancers is a potential further measure of screening performance. (orig.)

Proportional incidence and radiological review of large (T2+) breast cancers as surrogate indicators of screening programme performance

Energy Technology Data Exchange (ETDEWEB)

Ciatto, S.; Bernardi, D.; Pellegrini, M.; Borsato, G.; Peterlongo, P. [APSS, U.O. Senologia Clinica e Screening Mammografico, Dipartimento di Radiodiagnostica, Trento (Italy); Gentilini, M.A. [APSS, Servizio Osservatorio Epidemiologico, Direzione promozione ed educazione alla salute, Trento (Italy); Caumo, F. [Centro di Prevenzione Senologica, Verona (Italy); Frigerio, A. [CRR, Centro di Riferimento Regionale per lo Screening Mammografico, Torino (Italy); Houssami, N. [University of Sydney, Screening and Test Evaluation Program, School of Public Health, Sydney Medical School, Sydney (Australia)

2012-06-15

Surrogate measures of screening performance [e.g. interval cancer (IC) proportional incidence] allow timely monitoring of sensitivity and quality. This study explored measures using large (T2+) breast cancers as potential indicators of screening performance. The proportional incidence of T2+ cancers (observed/expected cases) in a population-based screening programme (Trento, 2001-2009) was estimated. A parallel review of 'negative' preceding mammograms for screen-detected T2+ and for all ICs, using 'blinded' independent readings and case-mixes (54 T2+, 50 ICs, 170 controls) was also performed. T2+ cancers were observed in 168 screening participants: 48 at first screen, 67 at repeat screening and 53 ICs. The T2+ estimated proportional incidence was 68% (observed/expected = 168/247), corresponding to an estimated 32% reduction in the rate of T2+ cancers in screening participants relative to that expected without screening. Majority review classified 27.8% (15/54) of T2+ and 28% (14/50) of ICs as screening error (P = 0.84), with variable recall rates amongst radiologists (8.8-15.2%). T2+ review could be integrated as part of quality monitoring and potentially prove more feasible than IC review for some screening services. circle Interval breast cancers, assumed as screening failures, are monitored to estimate screening performance circle Large (T2+) cancers at screening may also represent failed prior screening detection circle Analysis of T2+ lesions may be more feasible than assessing interval cancers circle Analysis of T2+ cancers is a potential further measure of screening performance. (orig.)

Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer

International Nuclear Information System (INIS)

Vodusek, Ana Lina; Novakovic, Srdjan; Stegel, Vida; Jereb, Berta

2011-01-01

Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. Our patient developed secondary breast cancer after the treatment for Hodgkin’s disease in childhood. DNA was isolated from the patients’ blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer

Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium.

Directory of Open Access Journals (Sweden)

Jirong Long

2010-06-01

Full Text Available Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals of 1.25 (1.20-1.31 per allele (P = 3.2 x 10(-25 in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR = 1.19, 95% CI = 1.09-1.31, P = 1.3 x 10(-4, 2,797 cases and 2,662 controls. SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures.

Expression of BMI-1 and Mel-18 in breast tissue--a diagnostic marker in patients with breast cancer.

Science.gov (United States)

Riis, Margit L H; Lüders, Torben; Nesbakken, Anne-Jorunn; Vollan, Hilde S; Kristensen, Vessela; Bukholm, Ida R K

2010-12-16

Polycomb Group (PcG) proteins are epigenetic silencers involved in maintaining cellular identity, and their deregulation can result in cancer. Expression of Mel-18 and Bmi-1 has been studied in tumor tissue, but not in adjacent non-cancerous breast epithelium. Our study compares the expression of the two genes in normal breast epithelium of cancer patients and relates it to the level of expression in the corresponding tumors as well as in breast epithelium of healthy women. A total of 79 tumors, of which 71 malignant tumors of the breast, 6 fibroadenomas, and 2 DCIS were studied and compared to the reduction mammoplastic specimens of 11 healthy women. In addition there was available adjacent cancer free tissue for 23 of the malignant tumors. The tissue samples were stored in RNAlater, RNA was isolated to create expression microarray profile. These two genes were then studied more closely first on mRNA transcription level by microarrays (Agilent 44 K) and quantitative RT-PCR (TaqMan) and then on protein expression level using immunohistochemistry. Bmi-1 mRNA is significantly up-regulated in adjacent normal breast tissue in breast cancer patients compared to normal breast tissue from noncancerous patients. Conversely, mRNA transcription level of Mel-18 is lower in normal breast from patients operated for breast cancer compared to breast tissue from mammoplasty. When protein expression of these two genes was evaluated, we observed that most of the epithelial cells were positive for Bmi-1 in both groups of tissue samples, although the expression intensity was stronger in normal tissue from cancer patients compared to mammoplasty tissue samples. Protein expression of Mel-18 showed inversely stronger intensity in tissue samples from mammoplasty compared to normal breast tissue from patients operated for breast cancer. Bmi-1 mRNA level is consistently increased and Mel-18 mRNA level is consistently decreased in adjacent normal breast tissue of cancer patients as compared

Chromosomal radiosensitivity in breast cancer patients and BRCA1 and 2 mutation carriers

International Nuclear Information System (INIS)

Vral, Anne

2004-01-01

Enhanced chromosomal radiosensitivity is observed in significant proportions of cancer patients. In breast cancer patients, this elevated sensitivity is confirmed in several independent studies with the G2 assay as well as with the GO micronucleus (MN) assay for peripheral blood lymphocytes (PBL). Enhanced chromosomal radiosensitivity is a common feature of sporadic breast cancer patients as well as breast cancer patients with a family history of the disease. Segregation analysis showed Mendelian heritability of chromosomal radiosensitivity. As mutations in the highly penetrant breast cancer predisposing genes, BRCA1 and 2, are only present in about 3-5 % of familial breast cancer patients, they cannot solely account for the high proportion of radiosensitive cases found among all breast cancer patients. A review on chromosomal radiosensitivity in BRCA1 and 2 mutation carriers shows that breast cancer patients with a BRCAl or 2 mutation are on the average more radiosensitive than healthy individuals, but not different from breast cancer patients without a BRCA mutation. The radiation response of healthy BRCA1/2 mutation carriers, on the contrary, is not significantly different from controls. Most studies performed on wild type and BRCA +/- EBV lymphoblastoid cell lines also could not demonstrate any differences in MN response between both groups. These findings suggest that mutations in BRCA 1 and 2 are not playing a major role in chromosomal radiosensitivity as measured by G2 and MN assay. The enhanced sensitivity observed in a substantial proportion of breast cancer patients, irrespective of a BRCA1/2 mutation or not, suggests that this feature may be related to the presence of other mutations in low penetrance breast cancer predisposing genes, which may be involved in the process of DNA damage. (author)

Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

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Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

2010-04-01

This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells.

Science.gov (United States)

Maturi, Varun; Enroth, Stefan; Heldin, Carl-Henrik; Moustakas, Aristidis

2018-05-10

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial-mesenchymal transition (EMT). Triple-negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple-negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR-Cas9-mediated 30 bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage-independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro-tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple-negative mesenchymal breast cancer cells into more differentiated, epithelial-like clones, but can reduce tumorigenic potential, suggesting that not all pro-tumorigenic actions of ZEB1 are linked to the EMT. © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Breast conservation treatment of early stage breast cancer: patterns of failure

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Leborgne, Felix; Leborgne, Jose H; Ortega, Bettys; Doldan, Raquel; Zubizarreta, Eduardo

1995-02-15

Purpose: This study retrospectively assesses the patterns of failure in conservatively treated early stage breast cancer patients by correlating various clinical, pathologic, and treatment-related factors with local, axillary, and distant relapse. Methods and Materials: Between 1973 and 1990, 796 patients (817 breasts) received breast conservation surgery followed by radiotherapy. Local recurrences were counted as events even if they occurred simultaneously or after the appearance of axillary or distant metastases. Results: The 10-year actuarial relative disease-free survival (DFS) rate for T1N0, T2N0, and T1-2N1 was 82%, 71%, and 54%, respectively. Stage N0 patients had a significant DFS advantage over N1 patients (p = 0.02). The 15-year actuarial local recurrence-free rate for T1 and T2 tumors was 82% and 87%, respectively (p = nonsignificant). Univariate analysis identified three significant risk factors for local relapse: (a) 48 breasts with tumors showing an extensive intraductal component had a crude local recurrence rate of 23% compared to 8% for 769 breasts without intraductal component (p 0.0016); (b) the actuarial 10-year local recurrence-free rate for patients under age 40 years was 64% compared to 88% for patients over 40 years (p < 0.0001); (c) the 10-year actuarial local recurrence-free rate for 416 postmenopausal women without adjuvant tamoxifen was 83% compared to 97% for 107 postmenopausal women with tamoxifen (p = 0.0479). Salvage therapy for operable local recurrent patients resulted in a 8-year actuarial DFS rate of 47%, significantly lower than that obtained with primary treatment. The incidence of axillary relapse as the first sign of recurrence was 2%, and could be correlated with the lack of axillary dissection (p < 0.0000005) and primary tumor size (p = 0.03). Radiotherapy to the axilla did not influence axillary relapse. Actuarial 5-year DFS rate after treatment of isolated axillary recurrence was 27%. Axillary failure was a marker for

Breast conservation treatment of early stage breast cancer: patterns of failure

International Nuclear Information System (INIS)

Leborgne, Felix; Leborgne, Jose H.; Ortega, Bettys; Doldan, Raquel; Zubizarreta, Eduardo

1995-01-01

Purpose: This study retrospectively assesses the patterns of failure in conservatively treated early stage breast cancer patients by correlating various clinical, pathologic, and treatment-related factors with local, axillary, and distant relapse. Methods and Materials: Between 1973 and 1990, 796 patients (817 breasts) received breast conservation surgery followed by radiotherapy. Local recurrences were counted as events even if they occurred simultaneously or after the appearance of axillary or distant metastases. Results: The 10-year actuarial relative disease-free survival (DFS) rate for T1N0, T2N0, and T1-2N1 was 82%, 71%, and 54%, respectively. Stage N0 patients had a significant DFS advantage over N1 patients (p = 0.02). The 15-year actuarial local recurrence-free rate for T1 and T2 tumors was 82% and 87%, respectively (p = nonsignificant). Univariate analysis identified three significant risk factors for local relapse: (a) 48 breasts with tumors showing an extensive intraductal component had a crude local recurrence rate of 23% compared to 8% for 769 breasts without intraductal component (p 0.0016); (b) the actuarial 10-year local recurrence-free rate for patients under age 40 years was 64% compared to 88% for patients over 40 years (p < 0.0001); (c) the 10-year actuarial local recurrence-free rate for 416 postmenopausal women without adjuvant tamoxifen was 83% compared to 97% for 107 postmenopausal women with tamoxifen (p = 0.0479). Salvage therapy for operable local recurrent patients resulted in a 8-year actuarial DFS rate of 47%, significantly lower than that obtained with primary treatment. The incidence of axillary relapse as the first sign of recurrence was 2%, and could be correlated with the lack of axillary dissection (p < 0.0000005) and primary tumor size (p = 0.03). Radiotherapy to the axilla did not influence axillary relapse. Actuarial 5-year DFS rate after treatment of isolated axillary recurrence was 27%. Axillary failure was a marker for

Association of common ATM variants with familial breast cancer in a South American population

International Nuclear Information System (INIS)

González-Hormazábal, Patricio; Jara, Lilian; Bravo, Teresa; Blanco, Rafael; Valenzuela, Carlos Y; Gómez, Fernando; Waugh, Enrique; Peralta, Octavio; Ortuzar, Waldo; Reyes, Jose M

2008-01-01

The ATM gene has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory. In this study, a full mutation analysis of the ATM gene was carried out in patients from 137 Chilean breast cancer families, of which 126 were BRCA1/2 negatives and 11 BRCA1/2 positives. We further perform a case-control study between the subgroup of 126 cases BRCA1/2 negatives and 200 controls for the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms. In the full mutation analysis we detected two missense variants and eight intronic polymorphisms. Carriers of the variant IVS24-9delT, or IVS38-8T>C, or 5557G>A showed an increase in breast cancer risk. The higher significance was observed in the carriers of IVS38-8T>C (OR = 3.09 [95%CI 1.11–8.59], p = 0.024). The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype confered a 3.19 fold increase in breast cancer risk (OR = 3.19 [95%CI 1.16–8.89], p = 0.021). The haplotype estimation suggested a strong linkage disequilibrium between the three markers (D' = 1). We detected only three haplotypes in the cases and control samples, some of these may be founder haplotypes in the Chilean population. The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype alone or in combination with certain genetic background and/or environmental factors, could modify the cancer risk by increasing genetic inestability or by altering the effect of the normal DNA damage response

Haemorheological Changes in African Breast Cancer Patients

African Journals Online (AJOL)

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complications, African patients with breast cancer may well be predisposed to thrombotic complications during illness. ... having breast cancer were studied. The patients were diagnosed by one of the authors from histological biopsy from the lump removed from the breast. None of ... statistics (Student's t-test for paired data.

Reduced expression of α-L-Fucosidase-1 (FUCA-1) predicts recurrence and shorter cancer specific survival in luminal B LN+ breast cancer patients.

Science.gov (United States)

Bonin, Serena; Parascandolo, Alessia; Aversa, Cinzia; Barbazza, Renzo; Tsuchida, Nobuo; Castellone, Maria Domenica; Stanta, Giorgio; Vecchio, Giancarlo

2018-03-16

The lysosomal enzyme α-L-Fucosidase-1 (FUCA-1) catalyzes the hydrolytic cleavage of terminal fucose residues. FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors as its inactivation perturbs the fucosylation of proteins involved in cell adhesion, migration and metastases. Negativity to FUCA-1 was significantly related to the development of later recurrences in breast cancer patients with lymph node involvement at diagnosis. Cancer specific survival of luminal B LN+ patients was influenced by FUCA-1 expression as luminal B LN+ patients with positive expression had a longer cancer specific survival. FUCA-1 mRNA expression was inversely related to cancer stage and lymph node involvement. WB and qPCR analysis of FUCA-1 expression in breast cancer-derived cell lines confirmed an inverse relationship with tumor aggressiveness. This study shows that, within LN+ breast cancer patients, FUCA-1 is able to identify a sub-set of non recurrent patients characterized by the positive expression of FUCA-1 and that, within luminal B LN+ patients, the expression of FUCA-1 predicts longer cancer specific survival. We have analyzed FUCA-1 in 305 breast cancer patients by Immunohistochemistry (IHC), and by qPCR in breast cancer patients and in breast cancer cell lines.

Contralateral breast cancer and other second malignancies in patients treated by breast-conserving therapy with radiation

International Nuclear Information System (INIS)

Kurtz, J.M.; Amalric, R.; Brandone, H.; Ayme, Y.; Spitalier, J.M.

1988-01-01

Metachronous contralateral breast cancers and other second malignancies were evaluated in 2,850 patients treated between 1960 and 1981 primarily with radiotherapy (RT) either alone or following breast-conserving surgery. One hundred eighty-four contralateral cancers were observed in 22,491 patient-years of observation (818 per 10(5) patient-years), with a cumulative probability of 4.5% at 5, 7.9% at 10, and 11% at 15 and 20 years. Compared to patients with unilateral tumors, those destined to develop contralateral cancers were younger (mean age 51.9 vs 56.6) and more often gave a family history of breast cancer. Contralateral breast cancers were more frequent for more extensive tumors (T3 10% vs T1-26%; with inflammatory signs 10.6% without 6%), and in patients with ipsilateral local recurrence (with 9.1%, without 5.6%). Patients with contralateral cancers had a significantly less favorable survival experience (15-year actuarial survival after primary therapy 42%) than patients without contralateral cancer (15-year survival 65.5%). In early stage patients treated with conservative surgery and RT, contralateral cancer was not prognostically more favorable than ipsilateral breast recurrence. Among 72 other second malignancies (320 per 10(5) patient-years) were 2 soft tissue sarcomas in the irradiated area. This corresponds to an incidence of 21 cases per 10(5) patient-years for survivors beyond the fifth year. The possible influence of RT on contralateral cancers and other second malignancies is discussed

Comparison of different non-invasive screening methods in the diagnosis of stage T/sub 1/ breast cancer

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Bartl, W; Euller, A; Pfersmann, C; Bernaschek, G; Breitenecker, G

1984-10-01

52 women with stage T/sub 1/ breast cancer were investigated by thermography, mammography and ultrasound and the results compared with the patients age, histological tumour type and the degree of malignancy. The best results were achieved by mammography (sensitivity: 85%). In tumours with a large amount of connective tissue (scirrhous or invasive lobular cancer) sensitivity rose to 94%, while in tumours with little connective tissue (solid, medullary, adenomatous and papillary) sensitivity decreased to 69%. The respective values for thermographic sensitivity were 44% and 77% and for ultrasound sensitivity in palpable tumours 85% and 65%, respectively. On mammography 3 carcinomas were not recognized, all three in younger patients; on thermography also three false negative results were obtained, but all in older patients. The sensitivity of thermography increases in parallel with increasing degree of tumour malignancy. Whilst ultrasound is a valuable aid for differential diagnosis in palpable tumours only, screening results can evidently be improved by a combination of thermography and mammography.

A comparison of different non-invasive screening methods in the diagnosis of stage T1 breast cancer

International Nuclear Information System (INIS)

Bartl, W.; Euller, A.; Pfersmann, C.; Bernaschek, G.; Breitenecker, G.

1984-01-01

52 women with stage T 1 breast cancer were investigated by thermography, mammography and ultrasound and the results compared with the patients age, histological tumour type and the degree of malignancy. The best results were achieved by mammography (sensitivity: 85%). In tumours with a large amount of connective tissue (scirrhous or invasive lobular cancer) sensitivity rose to 94%, whilst in tumours with little connective tissue (solid, medullary, adenomatous and papillary) sensitivity decreased to 69%. The respective values for thermographic sensitivity were 44% and 77% and for ultrasound sensitivity in palpable tumours 85% and 65%, respectively. On mammography 3 carcinomas were not recognized, all three in younger patients; on thermography also three false negative results were obtained, but all in older patients. The sensitivity of thermography increases in parallel with increasing degree of tumour malignancy. Whilst ultrasound is a valuable aid for differential diagnosis in palpable tumours only, screening results can evidently be improved by a combination of thermography and mammography. (Author)

Profile of thyroid hormones in breast cancer patients

Directory of Open Access Journals (Sweden)

P.P. Saraiva

2005-05-01

Full Text Available Estrogen involvement in breast cancer has been established; however, the association between breast cancer and thyroid diseases is controversial. Estrogen-like effects of thyroid hormone on breast cancer cell growth in culture have been reported. The objective of the present study was to determine the profile of thyroid hormones in breast cancer patients. Serum aliquots from 26 patients with breast cancer ranging in age from 30 to 85 years and age-matched normal controls (N = 22 were analyzed for free triiodothyronine (T3F, free thyroxine (T4F, thyroid-stimulating hormone (TSH, antiperoxidase antibody (TPO, and estradiol (E2. Estrogen receptor ß (ERß was determined in tumor tissues by immunohistochemistry. Thyroid disease incidence was higher in patients than in controls (58 vs 18%, P < 0.05. Subclinical hyperthyroidism was the most frequent disorder in patients (31%; hypothyroidism (8% and positive anti-TPO antibodies (19% were also found. Subclinical hypothyroidism was the only dysfunction (18% found in controls. Hyperthyroidism was associated with postmenopausal patients, as shown by significantly higher mean T3 and T4 values and lower TSH levels in this group of breast cancer patients than in controls. The majority of positive ERß tumors were clustered in the postmenopausal patients and all cases presenting subclinical hyperthyroidism in this subgroup concomitantly exhibited Erß-positive tumors. Subclinical hyperthyroidism was present in only one of 6 premenopausal patients. We show here that postmenopausal breast cancer patients have a significantly increased thyroid hormone/E2 ratio (P < 0.05, suggesting a possible tumor growth-promoting effect caused by this misbalance.

Metabolic Plasticity of Metastatic Breast Cancer Cells: Adaptation to Changes in the Microenvironment

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Rui V. Simões

2015-08-01

Full Text Available Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells, leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1 provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2 lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.

The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan.

Science.gov (United States)

Abdikhakimov, Abdulla; Tukhtaboeva, Mukaddas; Adilov, Bakhtiyar; Turdikulova, Shahlo

2016-01-01

Breast cancer is the most common malignancy in women and affects approximately 1 out of 8 females in the US. Risk of developing breast cancer is strongly influenced by genetic factors. Germ-line mutations in BRCA1 and BRCA2 genes are associated with 5-10% of breast cancer incidence. To reduce the risk of developing cancer and to increase the likelihood of early detection, carriers of BRCA1 or BRCA2 mutations are offered surveillance programs and effective preventive medical interventions. Identification of founder mutations of BRCA1/2 in high risk communities can have a significant impact on the management of hereditary cancer at the level of the national healthcare systems, making genetic testing more affordable and cost-effective. BRCA1 and BRCA2 mutations in breast cancer patients have not been characterized in the Uzbek population. This pilot study aimed to investigate the contribution of BRCA1 and BRCA2 mutation to early onset and familial cases of breast cancer in Uzbekistan. A total of 67 patients with breast cancer and 103 age-matched disease free controls were included in this study. Utilizing SYBR Green based real-time allele-specific PCR, we have analyzed DNA samples of patients with breast cancer and disease free controls to identify the following BRCA1 and BRCA2 mutations: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT. Three unrelated samples (4.5%) were found to be positive for the heterozygous 5382insCBRCA1 mutation, representing a possible founder mutation in the Uzbek population, supporting the need for larger studies examining the contribution of this mutation to breast cancer incidence in Uzbekistan. We did not find BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, and BRCA2 6174delT mutations. This preliminary evidence suggests a potential contribution of BRCA1 5382insC mutation to breast cancer development in Uzbek population. Taking into account a high disease penetrance in carriers of BRCA1 mutation, it seems

CD8+ T cell infiltration in breast and colon cancer: A histologic and statistical analysis.

Directory of Open Access Journals (Sweden)

James Ziai

Full Text Available The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections. We examined step sections of breast and colorectal cancer samples for CD8+ T cell prevalence by standard chromogenic immunohistochemistry to determine marker variability and inform practice of T cell biomarker assessment in formalin-fixed, paraffin-embedded (FFPE tissue samples. Stained sections were digitally imaged and CD8+ lymphocytes within defined regions of interest (ROI including the tumor and surrounding stroma were enumerated. Statistical analyses of CD8+ cell count variability using a linear model/ANOVA framework between patients as well as between levels within a patient sample were performed. Our results show that CD8+ T-cell distribution is highly homogeneous within a standard tissue sample in both colorectal and breast carcinomas. As such, cytotoxic T cell prevalence by immunohistochemistry on a single level or even from a subsample of biopsy fragments taken from that level can be considered representative of cytotoxic T cell infiltration for the entire tumor section within the block. These findings support the technical validity of biomarker strategies relying on CD8 immunohistochemistry.

Characterization of TRPS1 and ERAS as oncogenes implicated in breast cancer

Energy Technology Data Exchange (ETDEWEB)

Lopez Gonzalez, L.

2015-07-01

New high throughput technologies have made possible to identify putative oncogenes in breast cancer. In this project we aim to relate and characterise two novel putative oncogenes, ERAS and TRPS1, in their role in human breast cancer. TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression through repression of GATA-regulated genes, therefore acting as a tumour suppressor gene. Conversely, TRPS1 expression has been shown to be significantly elevated in luminal and in a lesser extent in basal breast cancer cells, presenting roles both as an oncogene and as a tumour suppressor gene in breast cancer development. The aim of this project is therefore to determine the characteristics of TRPS1 either as a putative novel human oncogene or as a tumour suppressor gene in breast cancer cells. To this aim, we have cloned a novel isoform of TRPS1 and introduced it into several breast cancer cell lines. Our results show that overexpression of this isoform of TRPS1 results in variations in motility in non-carcinogenic cell lines, as well as in a series of EMT-like changes such as the down-regulation of the EMT marker E-cadherin, both of which can be associated to an increase in malignancy, suggesting an oncogenic behaviour for TRPS1. Furthermore, our results suggest that constitutively active members of the RAS protein family induce the expression of TRPS1, establishing a relationship between both genes. We can conclude that the effects of TRPS1 overexpression are moderate, inducing some changes but not fully transforming the cells. Therefore we cannot confirm that TRPS1 is a putative oncogene in breast cancer. (Author)

Paradoxical Association of Postoperative Plasma Sphingosine-1-Phosphate with Breast Cancer Aggressiveness and Chemotherapy

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Rajesh Ramanathan

2017-01-01

Full Text Available Sphingosine-1-phosphate (S1P is a bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. This study analyzes plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to healthy control volunteers. 452 plasma S1P samples among 158 breast cancer patients, along with 20 healthy control volunteers, were analyzed. Mean S1P levels did not significantly differ between cancer patients and controls. Smoking was associated with higher S1P levels in cancer patients. Baseline S1P levels had weak inverse correlation with levels of the inflammatory mediator interleukin- (IL- 17 and CCL-2 and positive correlation with tumor necrosis factor alpha (TNF-α. Midpoint S1P levels during adjuvant therapy were lower than baseline, with near return to baseline after completion, indicating a relationship between chemotherapy and circulating S1P. While stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2-enriched and triple-negative breast cancer as compared to luminal-type breast cancer. Plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that postoperative plasma S1P levels do not reflect S1P secretion from resected breast cancer.

The progesterone receptor Val660→Leu polymorphism and breast cancer risk

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De Vivo, Immaculata; Hankinson, Susan E; Colditz, Graham A; Hunter, David J

2004-01-01

Recent evidence suggests a role for progesterone in breast cancer development and tumorigenesis. Progesterone exerts its effect on target cells by interacting with its receptor; thus, genetic variations, which might cause alterations in the biological function in the progesterone receptor (PGR), can potentially contribute to an individual's susceptibility to breast cancer. It has been reported that the PROGINS allele, which is in complete linkage disequilibrium with a missense substitution in exon 4 (G/T, valine→leucine, at codon 660), is associated with a decreased risk for breast cancer. Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 1252 cases and 1660 matched controls with the use of the Taqman assay. We did not observe any association of breast cancer risk with carrying the G/T (Val660→Leu) polymorphism (odds ratio 1.10, 95% confidence interval 0.93–1.30). In addition, we did not observe an interaction between this allele and menopausal status and family history of breast cancer as reported previously. Overall, our study does not support an association between the Val660→Leu PROGINS polymorphism and breast cancer risk

IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3.