|
1
|
Su Y, Dang NM, Depypere H, Santucci-Pereira J, Gutiérrez-Díez PJ, Kanefsky J, Janssens JP, Russo J. Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers. Eur J Cancer Prev 2023; 32:126-138. [PMID: 35881946 PMCID: PMC9800649 DOI: 10.1097/cej.0000000000000763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. METHODS We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. RESULTS We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. CONCLUSION Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.
Collapse
Affiliation(s)
- Yanrong Su
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Nhi M. Dang
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Herman Depypere
- Department of Gynecology, Breast and Menopause clinic, University Hospital of Ghent, Corneel Heymanslaan 10, 9000 Ghent, Belgium
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Julia Santucci-Pereira
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | | | - Joice Kanefsky
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Jaak Ph. Janssens
- European Cancer Prevention Organization, University of Hasselt, Klein Hilststraat 5, 3500 Hasselt, Belgium
| | - Jose Russo
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- Dr. Russo conceived the study and supervised the work. Dr. Russo passed away on September 24, 2021
| |
Collapse
|
|
2
|
Synovial gene signatures associated with the development of rheumatoid arthritis in at risk individuals: A prospective study. J Autoimmun 2022; 133:102923. [PMID: 36208493 DOI: 10.1016/j.jaut.2022.102923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/24/2022] [Accepted: 09/27/2022] [Indexed: 12/07/2022]
Abstract
OBJECTIVE To identify molecular changes in synovium before arthritis development in individuals at risk of developing rheumatoid arthritis (RA). MATERIALS AND METHODS We included 67 IgM rheumatoid factor and/or anti-citrullinated protein antibody positive individuals with arthralgia but without arthritis. Synovial biopsies were collected after which individuals were prospectively followed for at least 2 years during which 17 developed arthritis. An exploratory genome-wide transcriptional profiling study was performed in 13 preselected individuals to identify transcripts associated with arthritis development (n = 6). Findings were validated using quantitative real-time PCR and immunohistochemistry in the total cohort. RESULTS Microarray-based survival analyses identified 5588 transcripts whose expression levels in synovium were significantly associated with arthritis development. Pathway analysis revealed that synovial tissue of at risk individuals who later developed arthritis display higher expression of genes involved in adaptive immune response-related pathways compared to at risk individuals who did not develop arthritis. Lower expression was observed for genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism. Two-way hierarchical clustering analyses of a 27-gene signature separated the total at risk cohort into two groups, where pre-RA individuals preferred to cluster together. Immunohistochemistry studies revealed more podoplanin positive cells and lower lipid droplet staining in synovial tissue from pre-RA individuals. CONCLUSION Synovial alterations in adaptive immune response and lipid metabolism are associated with future development of arthritis. Since this data show synovial changes without overt cellular infiltration, these may be attributed to preclinical changes in resident synovial tissue cells such as fibroblasts, macrophages and tissue resident T cells.
Collapse
|
|
3
|
Custódio N, Savisaar R, Carvalho C, Bak-Gordon P, Ribeiro MI, Tavares J, Nunes PB, Peixoto A, Pinto C, Escudeiro C, Teixeira MR, Carmo-Fonseca M. Expression Profiling in Ovarian Cancer Reveals Coordinated Regulation of BRCA1/2 and Homologous Recombination Genes. Biomedicines 2022; 10:biomedicines10020199. [PMID: 35203410 PMCID: PMC8868827 DOI: 10.3390/biomedicines10020199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with BRCA1/2 mutations. Genetic tests for BRCA1/2 mutations are currently used in the clinic, but results can be inconclusive due to the high prevalence of rare DNA sequence variants of unknown significance. Most tests also fail to detect epigenetic modifications and mutations located deep within introns that may alter the mRNA. The aim of this study was to investigate whether quantitation of BRCA1/2 mRNAs in ovarian cancer can provide information beyond the DNA tests. Using the nCounter assay from NanoString Technologies, we analyzed RNA isolated from 38 ovarian cancer specimens and 11 normal fallopian tube samples. We found that BRCA1/2 expression was highly variable among tumors. We further observed that tumors with lower levels of BRCA1/2 mRNA showed downregulated expression of 12 additional HR genes. Analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed the coordinated expression of BRCA1/2 and HR genes. To facilitate the routine analysis of BRCA1/2 mRNA in the clinical setting, we developed a targeted droplet digital PCR approach that can be used with FFPE samples. In conclusion, this study underscores the potential clinical benefit of measuring mRNA levels in tumors when BRCA1/2 DNA tests are negative or inconclusive.
Collapse
Affiliation(s)
- Noélia Custódio
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
- Correspondence: ; Tel.: +35-121-799-9411
| | - Rosina Savisaar
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
| | - Célia Carvalho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
| | - Pedro Bak-Gordon
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
| | - Maria I. Ribeiro
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
| | - Joana Tavares
- Serviço de Anatomia Patológica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisboa, Portugal;
| | - Paula B. Nunes
- Hospital CUF Descobertas, 1998-018 Lisboa, Portugal;
- Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Ana Peixoto
- Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, 4200-072 Porto, Portugal; (A.P.); (C.P.); (C.E.); (M.R.T.)
| | - Carla Pinto
- Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, 4200-072 Porto, Portugal; (A.P.); (C.P.); (C.E.); (M.R.T.)
| | - Carla Escudeiro
- Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, 4200-072 Porto, Portugal; (A.P.); (C.P.); (C.E.); (M.R.T.)
| | - Manuel R. Teixeira
- Serviço de Genética, Instituto Português de Oncologia do Porto Francisco Gentil, 4200-072 Porto, Portugal; (A.P.); (C.P.); (C.E.); (M.R.T.)
| | - Maria Carmo-Fonseca
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (R.S.); (C.C.); (P.B.-G.); (M.I.R.); (M.C.-F.)
| |
Collapse
|
|
4
|
Yamaguchi H, Kitami K, Wu X, He L, Wang J, Wang B, Komatsu Y. Alteration of DNA Damage Response Causes Cleft Palate. Front Physiol 2021; 12:649492. [PMID: 33854442 PMCID: PMC8039291 DOI: 10.3389/fphys.2021.649492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Cleft palate is one of the most common craniofacial birth defects, however, little is known about how changes in the DNA damage response (DDR) cause cleft palate. To determine the role of DDR during palatogenesis, the DDR process was altered using a pharmacological intervention approach. A compromised DDR caused by a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor resulted in cleft palate in wild-type mouse embryos, with increased DNA damage and apoptosis. In addition, a mouse genetic approach was employed to disrupt breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), known as key players in DDR. An ectomesenchymal-specific deletion of Brca1 or Brca2 resulted in cleft palate due to attenuation of cell survival. This was supported by the phenotypes of the ectomesenchymal-specific Brca1/Brca2 double-knockout mice. The cleft palate phenotype was rescued by superimposing p53 null alleles, demonstrating that the BRCA1/2-p53 DDR pathway is critical for palatogenesis. Our study highlights the importance of DDR in palatogenesis.
Collapse
Affiliation(s)
- Hiroyuki Yamaguchi
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States
| | - Kohei Kitami
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States
| | - Xiao Wu
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Li He
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States
| | - Jianbo Wang
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States
| | - Bin Wang
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Graduate Program in Genetics & Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Yoshihiro Komatsu
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States.,Graduate Program in Genetics & Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| |
Collapse
|
|
5
|
Kitami K, Kitami M, Kaku M, Wang B, Komatsu Y. BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development. PLoS Genet 2018; 14:e1007340. [PMID: 29718910 PMCID: PMC5951594 DOI: 10.1371/journal.pgen.1007340] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 05/14/2018] [Accepted: 03/28/2018] [Indexed: 11/26/2022] Open
Abstract
Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1-deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo, indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation.
Collapse
Affiliation(s)
- Kohei Kitami
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States of America
- Division of Orthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Megumi Kitami
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States of America
| | - Masaru Kaku
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States of America
- Division of Bioprosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Bin Wang
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
- Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, United States of America
| | - Yoshihiro Komatsu
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States of America
- Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, United States of America
| |
Collapse
|
|
6
|
Abdelmegeed SM, Mohammed S. Canine mammary tumors as a model for human disease. Oncol Lett 2018; 15:8195-8205. [PMID: 29928319 PMCID: PMC6004712 DOI: 10.3892/ol.2018.8411] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 02/12/2018] [Indexed: 12/13/2022] Open
Abstract
Animal models for examining human breast cancer (HBC) carcinogenesis have been extensively studied and proposed. With the recent advent of immunotherapy, significant attention has been focused on the dog as a model for human cancer. Dogs develop mammary tumors and other cancer types spontaneously with an intact immune system, which exhibit a number of clinical and molecular similarities to HBC. In addition to the spontaneous tumor presentation, the clinical similarities between human and canine mammary tumors (CMT) include the age at onset, hormonal etiology and course of the diseases. Furthermore, factors that affect the disease outcome, including tumor size, stage and lymph node invasion, are similar in HBC and CMT. Similarly, the molecular characteristics of steroid receptor, epidermal growth factor, proliferation marker, metalloproteinase and cyclooxygenase expression, and the mutation of the p53 tumor suppressor gene in CMT, mimic HBC. Furthermore, ductal carcinomas in situ in human and canine mammary glands are particularly similar in their pathological, molecular and visual characteristics. These CMT characteristics and their similarities to HBC indicate that the dog could be an excellent model for the study of human disease. These similarities are discussed in detail in the present review, and are compared with the in vitro and other in vivo animal models available.
Collapse
Affiliation(s)
- Somaia M Abdelmegeed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
| | - Sulma Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
| |
Collapse
|
|
7
|
Mittal V, El Rayes T, Narula N, McGraw TE, Altorki NK, Barcellos-Hoff MH. The Microenvironment of Lung Cancer and Therapeutic Implications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 890:75-110. [PMID: 26703800 DOI: 10.1007/978-3-319-24932-2_5] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.
Collapse
MESH Headings
- Antibodies, Monoclonal/therapeutic use
- Antineoplastic Agents/therapeutic use
- Carcinogenesis/drug effects
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Cell Communication/drug effects
- Drug Resistance, Neoplasm/genetics
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Diseases, Obstructive/complications
- Lung Diseases, Obstructive/drug therapy
- Lung Diseases, Obstructive/genetics
- Lung Diseases, Obstructive/metabolism
- Lung Neoplasms/complications
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mesenchymal Stem Cells/drug effects
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Pulmonary Emphysema/complications
- Pulmonary Emphysema/drug therapy
- Pulmonary Emphysema/genetics
- Pulmonary Emphysema/metabolism
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
Collapse
Affiliation(s)
- Vivek Mittal
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
| | - Tina El Rayes
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Weill Cornell Graduate School of Medical Sciences, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Navneet Narula
- Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Timothy E McGraw
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Nasser K Altorki
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, New York University School of Medicine, 566 First Avenue, New York, NY, 10016, USA.
| |
Collapse
|
|
8
|
Segev Y, Rosen B, Lubinski J, Gronwald J, Lynch HT, Moller P, Kim-Sing C, Ghadirian P, Karlan B, Eng C, Gilchrist D, Neuhausen SL, Eisen A, Friedman E, Euhus D, Ping S, Narod SA, the Hereditary Breast Cancer Study Group. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. Fam Cancer 2015; 14:383-91. [PMID: 25838159 PMCID: PMC4962606 DOI: 10.1007/s10689-015-9798-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study.
Collapse
Affiliation(s)
- Yakir Segev
- Women’s College Research Institute, 790 Bay Street, Toronto, ON, M5G 1N8, Canada
- Department of Obstetrics and Gynecology, University of Toronto and Gynecologic Oncology, Princess Margaret Hospital, Toronto, ON, M5G 2M9, Canada
| | - Barry Rosen
- Department of Obstetrics and Gynecology, University of Toronto and Gynecologic Oncology, Princess Margaret Hospital, Toronto, ON, M5G 2M9, Canada
| | - Jan Lubinski
- International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Jacek Gronwald
- International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Henry T. Lynch
- Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, 68178 USA
| | - Pal Moller
- Inherited Cancer Research Group, The Norwegian Radium Hospital, Department for Medical Genetics, University Hospital, Oslo, Norway
| | | | - Parviz Ghadirian
- Epidemiology Research Unit, Research Centre of the University of Montreal Hospital Centre (CRCHUM), Montreal, QC, Canada
| | - Beth Karlan
- Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Beverly Hills, CA, USA
| | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Dawna Gilchrist
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| | - Susan L. Neuhausen
- Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Andrea Eisen
- Sunnybrook Regional Health Sciences Center, Toronto, ON, Canada
| | - Eitan Friedman
- Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel
| | - David Euhus
- Department of Surgery, John Hopkins University, Baltimore, MD, 21218, USA
| | - Sun Ping
- Women’s College Research Institute, 790 Bay Street, Toronto, ON, M5G 1N8, Canada
| | - Steven A. Narod
- Women’s College Research Institute, 790 Bay Street, Toronto, ON, M5G 1N8, Canada
| | | |
Collapse
|
|
9
|
Jeong JH, Jo A, Park P, Lee H, Lee HO. Brca2 deficiency leads to T cell loss and immune dysfunction. Mol Cells 2015; 38:251-8. [PMID: 25666348 PMCID: PMC4363725 DOI: 10.14348/molcells.2015.2302] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 12/03/2014] [Accepted: 12/04/2014] [Indexed: 12/19/2022] Open
Abstract
Germline mutations in the breast cancer type 2 susceptibility gene (BRCA2) are linked to familial breast cancer and the progressive bone marrow failure syndrome Fanconi anaemia. Established Brca2 mouse knockout models show embryonic lethality, but those with a truncating mutation at the C-terminus survive to birth and develop thymic lymphoma at an early age. To overcome early lethality and investigate the function of BRCA2, we used T cell-specific conditional Brca2 knockout mice, which were previously shown to develop thymic lymphoma at a low penetrance. In the current study we showed that the number of peripheral T cells, particularly naïve pools, drastically declined with age. This decline was primarily ascribed to improper peripheral maintenance. Furthermore, heterozygous mice with one wild-type Brca2 allele manifested reduced T cell numbers, suggesting that Brca2 haploinsufficiency might also result in T cell loss. Our study reveals molecular events occurring in Brca2-deficient T cells and suggests that both heterozygous and homozygous Brca2 mutation may lead to dysfunction in T cell populations.
Collapse
Affiliation(s)
- Jun-hyeon Jeong
- Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742,
Korea
| | - Areum Jo
- Samsung Genome Institute, Samsung Medical Center, Seoul 135-710,
Korea
- SAIHST, Sungkyunkwan University School of Medicine, Seoul 135-710,
Korea
| | - Pilgu Park
- Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742,
Korea
| | - Hyunsook Lee
- Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742,
Korea
| | - Hae-Ock Lee
- Samsung Genome Institute, Samsung Medical Center, Seoul 135-710,
Korea
- SAIHST, Sungkyunkwan University School of Medicine, Seoul 135-710,
Korea
| |
Collapse
|
|
10
|
Lu X, Deng Y, Huang L, Feng B, Liao B. A co-expression modules based gene selection for cancer recognition. J Theor Biol 2014; 362:75-82. [DOI: 10.1016/j.jtbi.2014.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 01/06/2014] [Accepted: 01/06/2014] [Indexed: 11/28/2022]
|
|
11
|
Manavathi B, Samanthapudi VSK, Gajulapalli VNR. Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development. Front Cell Dev Biol 2014; 2:34. [PMID: 25364741 PMCID: PMC4207046 DOI: 10.3389/fcell.2014.00034] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 07/21/2014] [Indexed: 12/14/2022] Open
Abstract
The steroid hormone, 17β-estradiol (E2), plays critical role in various cellular processes such as cell proliferation, differentiation, migration and apoptosis, and is essential for reproduction and mammary gland development. E2 actions are mediated by two classical nuclear hormone receptors, estrogen receptor α and β (ERs). The activity of ERs depends on the coordinated activity of ligand binding, post-translational modifications (PTMs), and importantly the interaction with their partner proteins called “coregulators.” Because coregulators are proved to be crucial for ER transcriptional activity, and majority of breast cancers are ERα positive, an increased interest in the field has led to the identification of a large number of coregulators. In the last decade, gene knockout studies using mouse models provided impetus to our further understanding of the role of these coregulators in mammary gland development. Several coregulators appear to be critical for terminal end bud (TEB) formation, ductal branching and alveologenesis during mammary gland development. The emerging studies support that, coregulators along with the other ER partner proteins called “pioneer factors” together contribute significantly to E2 signaling and mammary cell fate. This review discusses emerging themes in coregulator and pioneer factor mediated action on ER functions, in particular their role in mammary gland cell fate and development.
Collapse
Affiliation(s)
- Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad Hyderabad, India
| | | | | |
Collapse
|
|
12
|
BRCA1--conductor of the breast stem cell orchestra: the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer. Stem Cell Rev Rep 2012; 8:982-93. [PMID: 22426855 DOI: 10.1007/s12015-012-9354-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups.
Collapse
|
|
13
|
Kotsopoulos J, Lubinski J, Salmena L, Lynch HT, Kim-Sing C, Foulkes WD, Ghadirian P, Neuhausen SL, Demsky R, Tung N, Ainsworth P, Senter L, Eisen A, Eng C, Singer C, Ginsburg O, Blum J, Huzarski T, Poll A, Sun P, Narod SA. Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 2012; 14:R42. [PMID: 22405187 PMCID: PMC3446376 DOI: 10.1186/bcr3138] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Revised: 01/26/2012] [Accepted: 03/09/2012] [Indexed: 12/23/2022] Open
Abstract
Introduction Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. Methods We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. Results Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). Conclusions These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.
Collapse
|
|
14
|
Yeh ES, Yang TW, Jung JJ, Gardner HP, Cardiff RD, Chodosh LA. Hunk is required for HER2/neu-induced mammary tumorigenesis. J Clin Invest 2011; 121:866-79. [PMID: 21393859 PMCID: PMC3049391 DOI: 10.1172/jci42928] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 12/29/2010] [Indexed: 12/20/2022] Open
Abstract
Understanding the molecular pathways that contribute to the aggressive behavior of human cancers is a critical research priority. The SNF1/AMPK-related protein kinase Hunk is overexpressed in aggressive subsets of human breast, ovarian, and colon cancers. Analysis of Hunk(–/–) mice revealed that this kinase is required for metastasis of c-myc–induced mammary tumors but not c-myc–induced primary tumor formation. Similar to c-myc, amplification of the proto-oncogene HER2/neu occurs in 10%–30% of breast cancers and is associated with aggressive tumor behavior. By crossing Hunk(–/–) mice with transgenic mouse models for HER2/neu-induced mammary tumorigenesis, we report that Hunk is required for primary tumor formation induced by HER2/neu. Knockdown and reconstitution experiments in mouse and human breast cancer cell lines demonstrated that Hunk is required for maintenance of the tumorigenic phenotype in HER2/neu-transformed cells. This requirement is kinase dependent and resulted from the ability of Hunk to suppress apoptosis in association with downregulation of the tumor suppressor p27(kip1). Additionally, we find that Hunk is rapidly upregulated following HER2/neu activation in vivo and in vitro. These findings provide what we believe is the first evidence for a role for Hunk in primary tumorigenesis and cell survival and identify this kinase as an essential effector of the HER2/neu oncogenic pathway.
Collapse
Affiliation(s)
- Elizabeth S. Yeh
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| | - Thomas W. Yang
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| | - Jason J. Jung
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| | - Heather P. Gardner
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| | - Robert D. Cardiff
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| | - Lewis A. Chodosh
- Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA
| |
Collapse
|
|
15
|
From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res 2011; 21:245-57. [PMID: 21243011 DOI: 10.1038/cr.2011.11] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/PR(+) tumors.
Collapse
|
|
16
|
Rivera P, von Euler H. Molecular Biological Aspects on Canine and Human Mammary Tumors. Vet Pathol 2010; 48:132-46. [DOI: 10.1177/0300985810387939] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- P. Rivera
- Center of Clinical Comparative Oncology C3O, Department of Clinical Sciences, Division of Small Animals, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - H. von Euler
- Center of Clinical Comparative Oncology C3O, Department of Clinical Sciences, Division of Small Animals, Swedish University of Agricultural Sciences, Uppsala, Sweden
| |
Collapse
|
|
17
|
Saha T, Rih JK, Roy R, Ballal R, Rosen EM. Transcriptional regulation of the base excision repair pathway by BRCA1. J Biol Chem 2010; 285:19092-105. [PMID: 20185827 PMCID: PMC2885188 DOI: 10.1074/jbc.m110.104430] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Revised: 02/24/2010] [Indexed: 11/06/2022] Open
Abstract
Inactivation of the breast cancer susceptibility gene BRCA1 plays a significant role in the development of a subset of breast cancers, although the major tumor suppressor function of this gene remains unclear. Previously, we showed that BRCA1 induces antioxidant-response gene expression and protects cells against oxidative stress. We now report that BRCA1 stimulates the base excision repair pathway, a major mechanism for the repair of oxidized DNA, by stimulating the activity of key base excision repair (BER) enzymes, including 8-oxoguanine DNA glycosylase (OGG1), the DNA glycosylase NTH1, and the apurinic endonuclease redox factor 1/apurinic endonuclease 1 (REF1/APE1), in human breast carcinoma cells. The increase in BER enzyme activity appears to be due, primarily, to an increase in enzyme expression. The ability of BRCA1 to stimulate the expression of the three BER enzymes and to enhance NTH1 promoter activity was dependent upon the octamer-binding transcription factor OCT1. Finally, we found that OGG1, NTH1, and REF1/APE1 each contribute to the BRCA1 protection against oxidative stress due to hydrogen peroxide and that hydrogen peroxide stimulates the expression of BRCA1 and the three BER enzymes. These findings identify a novel mechanism through which BRCA1 may regulate the repair of oxidative DNA damage.
Collapse
Affiliation(s)
- Tapas Saha
- From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057
| | - Jeong Keun Rih
- From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057
| | - Rabindra Roy
- From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057
| | - Rahul Ballal
- From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057
| | - Eliot M. Rosen
- From the Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057
| |
Collapse
|
|
18
|
Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, Welcsh P. Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas. Mol Cancer 2009; 8:48. [PMID: 19602291 PMCID: PMC2719582 DOI: 10.1186/1476-4598-8-48] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Accepted: 07/14/2009] [Indexed: 12/25/2022] Open
Abstract
Background DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure. Results Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms. Conclusion Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.
Collapse
Affiliation(s)
- Elizabeth M Swisher
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Malone JL, Nelson AC, Lieberman R, Anderson S, Holt JT. Oestrogen-mediated phosphorylation and stabilization of BRCA2 protein in breast. J Pathol 2009; 217:380-8. [PMID: 19016568 DOI: 10.1002/path.2458] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Disease-associated BRCA2 mutations typically result in protein truncations that delete the phosphorylation-regulated S3291 BRCA2 domain that interacts with Rad51. BRCA2 hereditary breast cancers are usually ER(+), differing from BRCA1 hereditary cancers, which are usually ER(-). We studied BRCA2 protein expression and S3291 phosphorylation in normal breast tissues and in sporadic breast cancers and observed that BRCA2 is expressed and phosphorylated in normal breast and 10 ER(+) breast cancers but not in 10 ER(-) breast cancers. In order to study this correlation between ER and BRCA2 expression, we studied ER(+) breast cancer cell lines. We found that a rapid increase in BRCA2 S3291 phosphorylation occurs following 17-beta-oestradiol (E2) treatment. This increase seen in BRCA2 total and phospho-S3291 protein levels was found to be unaffected with cycloheximide pre-treatment, but decreased following tamoxifen, ICI 182,780 or roscovitine treatment. This suggests a requirement for ER and cdk (cyclin-dependent kinase) in mediating the increased protein levels. MCF7 cell cycle distribution analysis following E2, in both the presence and absence of roscovitine (a cdk inhibitor), did not demonstrate any changes during an 8 h period, which further supports our hypothesis that mitogenic effects of E2 are not predominant at early time points. Studies with MG132 proteasome inhibitor and siRNA to skp2 support a model in which skp2-mediated proteasomal degradation of BRCA2 rapidly degrades BRCA2 protein in the absence of hormone treatment, which likely inhibits this pathway. E2 was shown to improve survival of MCF7 cells upon radiation treatment and roscovitine partially reversed this effect. We have demonstrated that BRCA2 protein is specifically expressed in ER(+) breast cancers and are investigating a pathway that may show a link between E2 action and BRCA2 protein function in breast cancer.
Collapse
Affiliation(s)
- J L Malone
- Department of Pathology, University of Colorado at Denver (UCDHSC), Aurora, CO 80045, USA
| | | | | | | | | |
Collapse
|
|
20
|
Lee E, Ma H, McKean-Cowdin R, Van Den Berg D, Bernstein L, Henderson BE, Ursin G. Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study. Cancer Epidemiol Biomarkers Prev 2009; 17:3170-8. [PMID: 18990759 DOI: 10.1158/1055-9965.epi-08-0396] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Multiparity and breast-feeding reduce breast cancer risk, whereas oral contraceptive use may slightly increase breast cancer risk in the general population. However, the effects of these factors in BRCA1 and BRCA2 mutation carriers are less clear. METHODS Case patients were 1,469 women from Los Angeles County ages 20 to 49 years with newly diagnosed breast cancer. Control subjects were 444 women without breast cancer, individually matched to a subset of cases on race, age, and neighborhood. BRCA1/2 genes were sequenced in the cases, and odds ratios of breast cancer associated with various reproductive and hormonal factors in BRCA1/2 mutation carriers and noncarriers were estimated using multivariable logistic regression. RESULTS Ninety-four women had a deleterious BRCA1 or BRCA2 mutation. Number of full-term pregnancies was inversely associated with breast cancer risk regardless of BRCA1/2 mutation status. Longer breast-feeding duration was protective among noncarriers but not among mutation carriers; however, this apparent effect modification was not statistically significant (P = 0.23). Neither oral contraceptive use overall nor the use of low-dose oral contraceptives was associated with an increased risk of breast cancer in any subgroup. CONCLUSIONS Our results suggest that parity protects against breast cancer in BRCA1/2 mutation carriers, whereas breast-feeding does not. Our data suggest no association between oral contraceptive use and breast cancer risk in BRCA1/2 mutation carriers. Further confirmation that currently available low-dose oral contraceptives do not increase breast cancer risk in carriers is important from a public health perspective given the high prevalence of oral contraceptive use in the United States.
Collapse
Affiliation(s)
- Eunjung Lee
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Room 4407, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Klopfleisch R, Gruber AD. Increased Expression of BRCA2 and RAD51 in Lymph Node Metastases of Canine Mammary Adenocarcinomas. Vet Pathol 2009; 46:416-22. [DOI: 10.1354/vp.08-vp-0212-k-fl] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The BRCA/RAD51 complex of tumor suppressor genes plays a major role in the DNA damage response. In this explorative study, BRCA1, BRCA2, and RAD51 mRNA expression was quantified in highly defined laser microdissected tissue samples of simple adenomas, adenocarcinomas of the mammary gland, and their lymph node metastases by real-time quantitative reverse transcription polymerase chain reaction. Expression levels in the tumors were normalized to the geometric mean of 3 housekeeping genes and quantified relative to normal mammary epithelium of the same dog. In adenomas, mRNA expression was reduced for BRCA1 (6/10 dogs, 60%), BRCA2 (4/10 dogs, 40%), and RAD51 (4/10, 40%). In adenocarcinomas BRCA1 expression varied with increased expression in 3 of 10 (30%) dogs and no differences in 7 of 10 (70%) dogs when compared with normal mammary gland. BRCA2 and RAD51 were overexpressed in 5 of 10 (50%) and 6 of 10 (60%) of adenocarcinomas, respectively. An overexpression of RAD51 and BRCA2 was found in 8 of 10 (80%) and 5 of 10 (50%) of the lymph node metastases, respectively. Direct comparison of primary tumors and metastases revealed increased mRNA expression of BRCA1 (2/10 dogs, 20%), BRCA2 (2/10 dogs, 20%), and RAD51 (3/10 dogs, 30%) in lymph node metastases. Taken together, the results suggest that RAD51 is upregulated in the majority of lymph node metastases of canine mammary tumors. Further experimental studies are needed to clarify whether these changes in gene expression are a direct carcinogenetic stimulus or a protective response due to genetic instability during tumor progression.
Collapse
Affiliation(s)
- R. Klopfleisch
- Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Straße 15, 14163 Berlin, Germany
| | - A. D. Gruber
- Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Straße 15, 14163 Berlin, Germany
| |
Collapse
|
|
22
|
|
|
23
|
Abstract
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. Elucidating molecular mechanism of tissue- and gender-specific phenomena in BRCA1-related tumors is a key to our understanding of BRCA1 function in tumor suppression. This review summarizes studies in recent years on the link between BRCA1 and estrogen/progesterone signaling pathways, as well as discusses various models underscoring a triangle relationship among BRCA1, estrogen and genome instability.
Collapse
Affiliation(s)
- Yanfen Hu
- Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
| |
Collapse
|
|
24
|
Tan-Wong SM, French JD, Proudfoot NJ, Brown MA. Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene. Proc Natl Acad Sci U S A 2008; 105:5160-5. [PMID: 18375767 PMCID: PMC2278189 DOI: 10.1073/pnas.0801048105] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2007] [Indexed: 11/18/2022] Open
Abstract
The 85-kb breast cancer-associated gene BRCA1 is an established tumor suppressor gene, but its regulation is poorly understood. We demonstrate by gene conformation analysis in both human cell lines and mouse mammary tissue that gene loops are imposed on BRCA1 between the promoter, introns, and terminator region. Significantly, association between the BRCA1 promoter and terminator regions change upon estrogen stimulation and during lactational development. Loop formation is transcription-dependent, suggesting that transcriptional elongation plays an active role in BRCA1 loop formation. We show that the BRCA1 terminator region can suppress estrogen-induced transcription and so may regulate BRCA1 expression. Significantly, BRCA1 promoter and terminator interactions vary in different breast cancer cell lines, indicating that defects in BRCA1 chromatin structure may contribute to dysregulated expression of BRCA1 seen in breast tumors.
Collapse
Affiliation(s)
- Sue Mei Tan-Wong
- *Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom; and
| | - Juliet D. French
- School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia
| | - Nicholas J. Proudfoot
- *Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom; and
| | - Melissa A. Brown
- *Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom; and
- School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia
| |
Collapse
|
|
25
|
Antonova L, Mueller CR. Hydrocortisone down-regulates the tumor suppressor gene BRCA1 in mammary cells: a possible molecular link between stress and breast cancer. Genes Chromosomes Cancer 2008; 47:341-52. [PMID: 18196591 DOI: 10.1002/gcc.20538] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Psychological stress has been correlated with breast cancer development in numerous epidemiological studies. However, physiological and molecular models which may account for this association are not readily available. We have found that the stress hormone hydrocortisone (cortisol) down-regulates the expression of the breast cancer susceptibility gene BRCA1 in the nonmalignant mouse mammary cell line EPH4. This effect is concentration-dependent, is reliant on the continuous presence of hydrocortisone, and is not affected by the addition of lactogenic hormones, or growth conditions. Hydrocortisone was also found to negate a known positive effect of estrogen on BRCA1 expression and, therefore, may interfere with estrogen-related signaling in mammary epithelial cells. The repressive effect of hydrocortisone is diminished or lost in the mouse mammary lines HC-11 and SP1, respectively, suggesting regulation of the BRCA1 may differ between lines. We have uncovered two promoter regulatory sites, which are involved in BRCA1 regulation by hydrocortisone, namely the RIBS and UP regulatory elements. Binding of the transcription factor GABP to both sites is lost upon hydrocortisone addition, though the levels of these factors are not altered by hydrocortisone treatment. Because BRCA1 activity is important for a number of intracellular pathways involved in prevention of tumorigenesis, its observed down-regulation may represent a novel molecular mechanism for cortisol's involvement in breast cancer development.
Collapse
Affiliation(s)
- Lilia Antonova
- Queen's Cancer Research Institute, Queen's University, Kingston, ON, Canada
| | | |
Collapse
|
|
26
|
Gochhait S, Bukhari SIA, Bairwa N, Vadhera S, Darvishi K, Raish M, Gupta P, Husain SA, Bamezai RNK. Implication of BRCA2 -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by p53 codon 72 Arg>Pro polymorphism. Breast Cancer Res 2008; 9:R71. [PMID: 17945002 PMCID: PMC2242669 DOI: 10.1186/bcr1780] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2006] [Revised: 06/26/2007] [Accepted: 10/18/2007] [Indexed: 01/13/2023] Open
Abstract
Introduction The absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined. Methods The luciferase reporter assay followed by RNA secondary structure analysis was used for the functional characterization of -26 5' UTR G>A polymorphism in BRCA2. The genotype and the allele frequency for the polymorphisms were determined and relative risk adjusted for age was calculated in a case-control study of 576 individuals (243 patients and 333 controls) from north India. Results -26 G>A polymorphism in the 5' UTR of BRCA2 was found to be functional whereby the A allele increased the reporter gene expression by twice that of the G allele in MCF-7 (P = 0.003) and HeLa (P = 0.013) cells. RNA secondary structure analysis by two different programs predicted the A allele to alter the stability of a loop in the vicinity of the translation start site. Its direct implication in breast cancer became evident by a case-control study in which the heterozygous genotype was found to be protective in nature (Pheterozygote advantage model = 0.0005, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.4 to 0.8), which was further supported by trends observed in a genomic instability study. The p53 codon 72 Arg homozygous genotype was found to be over-represented in patients (P = 0.0005, OR = 2.3, 95% CI = 1.4 to 3.6). The interaction study indicated an increased protection under simultaneous presence of protector genotypes of both the polymorphic loci (P = 0.0001, OR = 0.2, 95% CI = 0.1 to 0.4). Conclusion Our study shows that -26 5' UTR polymorphism in BRCA2 can modulate the fine-tuned regulation of the multifunctional gene BRCA2 and renders risk or protection according to the genotype status in the sporadic form of breast cancer, which is further influenced by the germline genetic backgrounds of codon 72 polymorphism of p53.
Collapse
Affiliation(s)
- Sailesh Gochhait
- National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, Aruna Asafali Road, New Delhi-110067, India
| | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Prolactin levels, breast-feeding and milk production in a cohort of young healthy women from high-risk breast cancer families: implications for breast cancer risk. Fam Cancer 2007; 7:221-8. [DOI: 10.1007/s10689-007-9178-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2007] [Accepted: 11/30/2007] [Indexed: 12/19/2022]
|
|
28
|
|
|
29
|
Lee SA, Baker MD. Analysis of DNA repair and recombination responses in mouse cells depleted for Brca2 by SiRNA. DNA Repair (Amst) 2007; 6:809-17. [PMID: 17336596 DOI: 10.1016/j.dnarep.2007.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2006] [Revised: 01/04/2007] [Accepted: 01/17/2007] [Indexed: 11/27/2022]
Abstract
The tumor suppressor BRCA2 is considered to play an important role in the maintenance of genome integrity through the repair of DNA lesions by homologous recombination. A mechanistic understanding of BRCA2 has been complicated by the embryonic lethality of mice bearing allelic knockouts of Brca2, and by variation in the DNA damage response in cells bearing BRCA2 deficiencies. It would be advantageous to develop approaches that avoid the cell lethality associated with complete inactivation of the gene, or the use of established tumor cell lines in which other genes in addition to BRCA2 may be mutant. In this study, SiRNA was used in stable transformation assays to knockdown Brca2 in mouse hybridoma cells by at least 75%. The Brca2-depleted cells were analyzed with respect to cell growth, sensitivity to DNA damaging agents (mitomycin C, methylmethane sulfonate, or ionizing radiation), intrachromosomal homologous recombination and gene targeting. Although the effect of Brca2-depletion on cell growth and sensitivity to DNA damaging agents was modest, the Brca2-depleted cells did show a significant shift in homologous recombination from gene conversion to single-strand annealing and a significant decrease in the efficiency of gene targeting. Both of these phenotypes are consistent with the proposed role of Brca2 in DNA repair and recombination.
Collapse
Affiliation(s)
- Shauna A Lee
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, Ontario, Canada N1G 2W1
| | | |
Collapse
|
|
30
|
Kotsopoulos J, Lubinski J, Lynch HT, Klijn J, Ghadirian P, Neuhausen SL, Kim-Sing C, Foulkes WD, Moller P, Isaacs C, Domchek S, Randall S, Offit K, Tung N, Ainsworth P, Gershoni-Baruch R, Eisen A, Daly M, Karlan B, Saal HM, Couch F, Pasini B, Wagner T, Friedman E, Rennert G, Eng C, Weitzel J, Sun P, Narod SA, Garber J, Osborne M, Fishman D, McLennan J, McKinnon W, Merajver S, Olsson H, Provencher D, Pasche B, Evans G, Meschino WS, Lemire E, Chudley A, Rayson D, Bellati C. Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2007; 105:221-8. [PMID: 17245541 DOI: 10.1007/s10549-006-9441-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 10/24/2006] [Indexed: 10/23/2022]
Abstract
An early age at first full-term birth is associated with a reduction in the subsequent development of breast cancer among women in the general population. A similar effect has not yet been reported among women who carry an inherited BRCA1 or BRCA2 mutation. We conducted a matched case-control study on 1816 pairs of women with a BRCA1 (n = 1405) or BRCA2 (n = 411) mutation in an attempt to elucidate the relationship between age at first full-term pregnancy and the risk of developing breast cancer. Information about the age at first childbirth and other pregnancy-related variables was derived from a questionnaire administered to women during the course of genetic counselling. There was no difference in the mean age at first full-term birth in the cases and controls (24.9 years vs. 24.8 years; P = 0.81, respectively). Compared to women whose first child was born at or before 18 years of age, a later age at first full-term birth did not influence the risk of developing breast cancer (OR = 1.00 per year; 95% CI 0.98-1.03; P-trend = 0.67). Stratification by mutation status did not affect the results. These findings suggest that an early first full-term birth does not confer protection against breast cancer in BRCA mutation carriers. Nonetheless, BRCA mutation carriers opting for a prophylactic oophorectomy as a breast and/or ovarian cancer risk-reducing strategy should complete childbearing prior to age 40 when this prevention modality is most effective.
Collapse
Affiliation(s)
- Joanne Kotsopoulos
- Centre for Research in Women's Health, Women's College Hospital, University of Toronto, Room 750, 790 Bay Street, 7th Floor, Toronto, ON M5G 1N8, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
McLaughlin JR, Risch HA, Lubinski J, Moller P, Ghadirian P, Lynch H, Karlan B, Fishman D, Rosen B, Neuhausen SL, Offit K, Kauff N, Domchek S, Tung N, Friedman E, Foulkes W, Sun P, Narod SA. Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 2007; 8:26-34. [PMID: 17196508 DOI: 10.1016/s1470-2045(06)70983-4] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. METHODS We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. FINDINGS Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0.56 [95% CI 0.45-0.71]; p<0.0001) and carriers of BRCA2 mutations (0.39 [0.23-0.66]; p=0.0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0.67 [0.46-0.96]; p=0.03), but with an increased risk for those with BRCA2 mutations (2.74 [1.18-6.41]; p=0.02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0.74 [0.56-0.97]; p=0.03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0.72 [0.41-1.29]; p=0.27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0.80 [0.59-1.08]; p=0.15), or for carriers of BRCA2 mutations (0.63 [0.34-1.15]; p=0.13). INTERPRETATION Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.
Collapse
|
|
32
|
Lu Y, Amleh A, Sun J, Jin X, McCullough SD, Baer R, Ren D, Li R, Hu Y. Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells. Mol Endocrinol 2006; 21:651-63. [PMID: 17185394 DOI: 10.1210/me.2006-0188] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Germ-line mutations in BRCA1 predispose women to early-onset, familial breast and ovarian cancers. However, BRCA1 expression is not restricted to breast and ovarian epithelial cells. For example, ovarian BRCA1 expression is enriched in ovarian granulosa cells, which are responsible for ovarian estrogen production in premenopausal women. Furthermore, recent tissue culture and animal studies suggest a functional role of BRCA1 in ovarian granulosa cells. Although levels of BRCA1 are known to fluctuate significantly during folliculogenesis and steroidogenesis, the mechanism by which BRCA1 expression is regulated in granulosa cells remains to be elucidated. Here we show that the ubiquitin-proteasome degradation pathway plays a significant role in the coordinated protein stability of BRCA1 and its partner BARD1 in ovarian granulosa cells. Our work identifies the amino-terminal RING domain-containing region of BRCA1 as the degron sequence that is both necessary and sufficient for polyubiquitination and proteasome-mediated protein degradation. Interestingly, mutations in the RING domain that abolish the ubiquitin E3 ligase activity of BRCA1 do not affect its own ubiquitination or degradation in ovarian granulosa cells. The proteasome-mediated degradation of BRCA1 and BARD1 also occurs during the cAMP-dependent steroidogenic process. Thus, the dynamic changes of BRCA1/BARD1 protein stability in ovarian granulosa cells provide an excellent paradigm for investigating the regulation of this protein complex under physiological conditions.
Collapse
Affiliation(s)
- Yunzhe Lu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Fan S, Meng Q, Auborn K, Carter T, Rosen EM. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 2006; 94:407-26. [PMID: 16434996 PMCID: PMC2361140 DOI: 10.1038/sj.bjc.6602935] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-α) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time- and dose-dependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 μM) and genistein (0.5–1.0 μM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-α activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.
Collapse
Affiliation(s)
- S Fan
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057-1469, USA
| | - Q Meng
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057-1469, USA
| | - K Auborn
- Department of Otolaryngology, North Shore-Long Island Jewish Research Institute, BoasMarks Biomedical Science Research Center, 350 Community Drive, Manhasset, New York 11030, USA
| | - T Carter
- Department of Otolaryngology, North Shore-Long Island Jewish Research Institute, BoasMarks Biomedical Science Research Center, 350 Community Drive, Manhasset, New York 11030, USA
| | - E M Rosen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057-1469, USA
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057-1469, USA. E-mail:
| |
Collapse
|
|
34
|
Kotsopoulos J, Lubinski J, Lynch HT, Neuhausen SL, Ghadirian P, Isaacs C, Weber B, Kim-Sing C, Foulkes WD, Gershoni-Baruch R, Ainsworth P, Friedman E, Daly M, Garber JE, Karlan B, Olopade OI, Tung N, Saal HM, Eisen A, Osborne M, Olsson H, Gilchrist D, Sun P, Narod SA. Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Causes Control 2006; 16:667-74. [PMID: 16049805 DOI: 10.1007/s10552-005-1724-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2004] [Accepted: 02/03/2005] [Indexed: 11/26/2022]
Abstract
Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was < or =11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.
Collapse
Affiliation(s)
- Joanne Kotsopoulos
- Centre for Research in Women's Health, University of Toronto, Women's College Hospital, 790 Bay Street, 7th Floor, Totonto, Ontario M5G 1N8, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG. Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity. Cancer Res 2005; 65:6557-67. [PMID: 16061635 DOI: 10.1158/0008-5472.can-05-0486] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ERalpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERalpha binding. Cyclin D1 and BRCA1 were both capable of binding ERalpha in a common region of the ERalpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1-mediated ERalpha transcriptional repression. In chromatin immunoprecipitation assays, 17beta-estradiol (E2) enhanced ERalpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERalpha recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERalpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ERalpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.
Collapse
Affiliation(s)
- Chenguang Wang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Thangaraju M, Rudelius M, Bierie B, Raffeld M, Sharan S, Hennighausen L, Huang AM, Sterneck E. C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development 2005; 132:4675-85. [PMID: 16192306 DOI: 10.1242/dev.02050] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The STAT3 transcription factor is an important initiator of mammary gland involution in the mouse. This work shows that the STAT3 target gene CCAAT/enhancer binding protein delta (C/EBPdelta) is a crucial mediator of pro-apoptotic gene expression events in mammary epithelial cells. In the absence of C/EBPdelta, involution is delayed, the pro-apoptotic genes encoding p53, BAK, IGFBP5 and SGP2/clusterin are not activated, while the anti-apoptotic genes coding for BFL1 and Cyclin D1 are not repressed. Consequently, p53 targets such as survivin, BRCA1, BRCA2 and BAX are not regulated appropriately and protease activation is delayed. Furthermore, expression of MMP3 and C/EBPdelta during the second phase of involution is perturbed in the absence of C/EBPdelta. In HC11 cells, C/EBPdelta alone is sufficient to induce IGFBP5 and SGP2. It also suppresses Cyclin D1 expression and cooperates with p53 to elicit apoptosis. This study places C/EBPdelta between STAT3 and several pro- and anti-apoptotic genes promoting the physiological cell death response in epithelial cells at the onset of mammary gland involution.
Collapse
Affiliation(s)
- Muthusamy Thangaraju
- Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Hu Y, Ghosh S, Amleh A, Yue W, Lu Y, Katz A, Li R. Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene 2005; 24:8343-8. [PMID: 16170371 DOI: 10.1038/sj.onc.1208985] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mutations in BRCA1 increase risks of familial breast and ovarian cancers, particularly among premenopausal women. While BRCA1 plays an active role in DNA repair, this function alone may not be sufficient to explain why BRCA1-associated tumors predominantly occur in estrogen-responsive tissues. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and a key target in breast cancer treatment. Aromatase expression in ovarian granulosa cells dictates levels of circulating estrogen in premenopausal women, and its aberrant overexpression in breast adipose tissues promotes breast cancer growth. Here, we show that BRCA1 modulates aromatase expression in ovarian granulosa cells and primary preadipocytes. The cyclic AMP-dependent expression of aromatase in ovarian granulosa cells is inversely correlated with the protein level of BRCA1. Importantly, transient knockdown of BRCA1 enhances aromatase expression in both ovarian granulosa cells and primary preadipocytes. We propose that BRCA1 deficiency in epithelial and certain nonepithelial cells may result in combined effects of aberrant estrogen biosynthesis and compromised DNA repair capability, which in turn may lead to specific cancers in the breast and ovary.
Collapse
Affiliation(s)
- Yanfen Hu
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Ma Y, Katiyar P, Jones LP, Fan S, Zhang Y, Furth PA, Rosen EM. The breast cancer susceptibility gene BRCA1 regulates progesterone receptor signaling in mammary epithelial cells. Mol Endocrinol 2005; 20:14-34. [PMID: 16109739 PMCID: PMC4031608 DOI: 10.1210/me.2004-0488] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The progesterone receptor (PR) plays roles in normal mammary development and breast cancer formation, where it may exert both stimulatory and inhibitory actions. Previously, the breast cancer susceptibility gene product BRCA1 was found to interact with and inhibit the transcriptional activity of estrogen receptor-alpha. In this study, we found that exogenous wild-type BRCA1 inhibited the activity of the PR in transient transfection assays utilizing a mouse mammary tumor virus-Luc reporter. Wild-type BRCA1 inhibited the activity of endogenous PR in human breast cancer cells (T47D and MCF-7) and inhibited the activity of exogenous PR-A, PR-B, and [PR-A plus PR-B] isoforms. On the other hand, knockdown of endogenous BRCA1 using small interfering RNA enhanced the progesterone-stimulated activity of the PR by about 4-fold. We documented an in vivo association of the endogenous BRCA1 with PR isoforms A and B and a direct in vitro interaction between BRCA1 and PR, which was partially mapped. Whereas down-regulation of the coactivator p300 contributes to the BRCA1-mediated repression of estrogen receptor-alpha, this mechanism does not contribute to inhibition of PR activity, because exogenous p300 did not rescue the BRCA1 repression of PR activity. The BRCA1-PR interaction has functional consequences. Thus, we showed that BRCA1 inhibits the expression of various endogenous progesterone-responsive genes and inhibits progesterone-stimulated proliferation of T47D cells. Finally, exogenous progesterone caused an exaggerated proliferative response in the mammary glands of mice harboring a mammary-targeted conditional deletion of the full-length isoform of Brca1. These findings suggest that BRCA1 regulates the activity of progesterone, a major hormone of pregnancy that may also participate in mammary carcinogenesis.
Collapse
Affiliation(s)
- Yongxian Ma
- Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057-1469, USA
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Aghmesheh M, Edwards L, Clarke CL, Byth K, Katzenellenbogen BS, Russell PJ, Friedlander M, Tucker KM, de Fazio A. Expression of steroid hormone receptors in BRCA1-associated ovarian carcinomas. Gynecol Oncol 2005; 97:16-25. [PMID: 15790432 DOI: 10.1016/j.ygyno.2004.12.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2004] [Indexed: 10/25/2022]
Abstract
OBJECTIVE BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERalpha and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERalpha and other hormone receptors in BRCA1-associated ovarian cancer was unknown. METHODS Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. RESULTS ERalpha expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERalpha and ERbeta were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. CONCLUSION Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.
Collapse
Affiliation(s)
- Morteza Aghmesheh
- Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Xu J, Fan S, Rosen EM. Regulation of the estrogen-inducible gene expression profile by the breast cancer susceptibility gene BRCA1. Endocrinology 2005; 146:2031-47. [PMID: 15637295 DOI: 10.1210/en.2004-0409] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The tumor suppressor gene BRCA1 functions in part as a caretaker in preserving the integrity of the genome, but also exhibits tissue-specific function by inhibiting estrogen receptor activity. Because estrogen (E2) induces a wide range of gene expression changes (by nongenomic and several transcriptional pathways), we sought to determine how comprehensive is the BRCA1-mediated inhibition of E2-induced gene expression alterations. Using cDNA-spotted microarrays, we identified a relatively large number of gene expression alterations (both increased and decreased expression) in MCF-7 cells caused by E2, some of which have been reported in previous studies. However, in the presence of exogenous wild-type BRCA1 (wtBRCA1), the response to E2 was severely blunted, with only about 10% the number of gene expression changes as that found in the absence of wtBRCA1. Examples of these findings were confirmed by semiquantitative and quantitative RT-PCR assays. In contrast to wtBRCA1, the induction by E2 of several E2-responsive genes was not inhibited by a full-length tumor-associated mutant BRCA1 protein [T300G (or (61)Cys-->Gly)]. For three E2-responsive genes whose induction by E2 was inhibited by wtBRCA1, wtBRCA1 had little or no effect on the mRNA half-life in the presence of E2. Consistent with these findings, wtBRCA1 inhibited E2-stimulated proliferation of MCF-7 cells, but wtBRCA1 failed to inhibit the proliferation of MCF-7 cells stimulated by IGF-I. Our findings suggest that BRCA1 globally inhibits the response to estrogen in a dose- and time-dependent fashion. The implications of these findings for understanding how BRCA1 may act to restrain E2 action in vivo are considered.
Collapse
Affiliation(s)
- Jingwen Xu
- Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road Northwest, Box 571469, Washington, D.C. 20057-1469, USA
| | | | | |
Collapse
|
|
41
|
Bae I, Fan S, Meng Q, Rih JK, Kim HJ, Kang HJ, Xu J, Goldberg ID, Jaiswal AK, Rosen EM. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res 2004; 64:7893-909. [PMID: 15520196 DOI: 10.1158/0008-5472.can-04-1119] [Citation(s) in RCA: 175] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.
Collapse
Affiliation(s)
- Insoo Bae
- Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057-1469, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Feng Z, Kachnic L, Zhang J, Powell SN, Xia F. DNA damage induces p53-dependent BRCA1 nuclear export. J Biol Chem 2004; 279:28574-84. [PMID: 15087457 DOI: 10.1074/jbc.m404137200] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The tumor suppressor gene BRCA1 plays an important role in the response to DNA damage. BRCA1 function is regulated by a variety of mechanisms including transcriptional control, phosphorylation, and protein-protein interactions. Recent studies have shown that BRCA1 is a nuclear-cytoplasmic shuttle protein. Its subcellular localization is controlled by a nuclear localization signal-mediated nuclear import via the importin receptor pathway and a nuclear export signal-facilitated nuclear export through a CRM1-dependent pathway. Using the human breast cancer cell line, MCF7, the subcellular distribution of BRCA1 was assessed by immunohistochemical staining and Western blotting analyses of fractionated subcellullar extracts. Ionizing radiation stimulated BRCA1 nuclear export in a dose-dependent manner. This DNA damage-induced BRCA1 nuclear export utilized a CRM1-dependent mechanism and also required wild-type p53, whose function was abrogated by the E6 protein in MCF7 cells. In addition, the dependence on p53 was confirmed using a second cell type operating a tetracycline-inducible system. The effect of ionizing radiation on BRCA1 export was observed in every phase of the cell cycle, although BRCA1 localization did vary between the G(1), S, and G(2)/M phases. These results imply that, in addition to ATM-, ATR-, and Chk2-dependent phosphorylations, cytoplasmic relocalization of BRCA1 protein is a mechanism whereby BRCA1 function is regulated in response to DNA damage.
Collapse
Affiliation(s)
- Zhihui Feng
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | | | | | | | | |
Collapse
|
|
43
|
Abstract
Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.
Collapse
Affiliation(s)
- Darcy L Thull
- Magee/UPCI Breast Cancer Genetics Program, Magee-Women's Hospital, Pittsburgh, Pennsylvania 15213, USA
| | | |
Collapse
|
|
44
|
Cheung AMY, Elia A, Tsao MS, Done S, Wagner KU, Hennighausen L, Hakem R, Mak TW. Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/-) mutant mice. Cancer Res 2004; 64:1959-65. [PMID: 15026330 DOI: 10.1158/0008-5472.can-03-2270] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Brca2 is an important tumor suppressor associated with susceptibility to breast cancer. Although increasing evidence indicates that the primary function of Brca2 is to facilitate the repair of DNA damage via the homologous recombination pathway, how Brca2 prevents breast cancer is largely unknown. To study the role of Brca2 specifically in mammary epithelium development, we crossed mice bearing the conditionally deficient allele Brca2(flox9-10) to mouse mammary tumor virus- or whey acidic protein-Cre transgenic lines. Analysis of these animals showed that Brca2 is not required for epithelial expansion in mammary glands of pregnant mice. In addition, examination of mammary gland involution revealed normal kinetics of mammary alveolar cell apoptosis after weaning of litters. Nevertheless, Brca2-deficient mice developed mammary adenocarcinomas after a long latency (average, 1.6 years). Detailed histopathological analysis of four of these tumors demonstrated that three of them showed abnormal p53 protein expression. A mutation in the p53 gene was detected in one case. Moreover, homozygosity versus heterozygosity for the Brca2 mutation heavily skewed the tumor spectrum toward mammary adenocarcinoma development in p53(+/-) mice. Our data indicate that Brca2 is not essential for mammary epithelium development but that Brca2 deficiency and down-regulated p53 expression can work jointly to promote mammary tumorigenesis.
Collapse
Affiliation(s)
- Alison M Y Cheung
- Advanced Medical Discovery Institute, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Whitehouse C, Chambers J, Catteau A, Solomon E. Brca1 expression is regulated by a bidirectional promoter that is shared by the Nbr1 gene in mouse. Gene 2004; 326:87-96. [PMID: 14729266 DOI: 10.1016/j.gene.2003.10.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The lack of functionally disrupting mutations of BRCA1 in sporadic breast tumours has suggested that other mechanisms, including dysregulation of gene expression, might be important in tumour development. We have analysed the control of expression of murine Brca1 and the adjacent gene, Nbr1, which lie head-to-head and are separated by less than 300 bp. Our results show that the expression of these two genes is under complex regulation, through a bidirectional promoter. Brca1 expression is driven by this single promoter, whereas Nbr1 expression is driven by this and one additional promoter, which generate two distinct transcripts, differing by the alternate use of the first exons. By comparison of mRNA transcription in adult murine tissues and also in the mammary gland during pregnancy and lactation, we show that Brca1 and Nbr1 expression is coordinately regulated in a spatial and temporal manner to produce quite different patterns of expression, even from the same promoter. The analysis of the murine and human syntenic region and its control has important implications for the regulation of human and murine BRCA1/NBR1 expression and the interpretation of animal models of disease.
Collapse
Affiliation(s)
- Caroline Whitehouse
- Department of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, Guy's Hospital, 8th Floor, Guy's Tower, London SE1 9RT, UK.
| | | | | | | |
Collapse
|
|
46
|
Mote PA, Leary JA, Avery KA, Sandelin K, Chenevix-Trench G, Kirk JA, Clarke CL. Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A. Genes Chromosomes Cancer 2004; 39:236-48. [PMID: 14732925 DOI: 10.1002/gcc.10321] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast and ovarian cancer, yet little is known of how disruptions in the functions of the proteins these genes encode increased cancer risk preferentially in hormone-dependent tissue. There is no information on whether a germ-line mutation in BRCA1 or BRCA2 causes disruptions in hormone-signaling pathways in the normal breast. In this study markers of hormone responsiveness were measured in prophylactically removed normal breast tissue (n = 31) in women bearing a germ-line pathogenic mutation in one of the BRCA genes. The estrogen receptor (ER) and proteins associated with ER action in hormone-sensitive tissues, namely, PS2 and the progesterone receptor (PR), were detected immunohistochemically. ER expression was not different in BRCA mutation carriers than in noncarriers, but there was a reduction in PS2 expression. PR expression was also reduced, and there was a striking lack of expression of the PRB isoform, which resulted in cases with PRA-only expression in BRCA1 and BRCA2 mutation carriers. The alterations in PS2 and PR expression were similar in the BRCA1 and BRCA2 carriers, demonstrating that although these proteins are structurally and functionally distinct, there is overlap in their interaction with hormone-signaling pathways. This study provides evidence for altered cell function arising from loss of function of one BRCA allele in the normal breast, leading to PS2 loss, preferential PRB loss, and expression of PRA alone. In breast cancer development, PRA overexpression becomes evident in premalignant lesions and is associated with features of poor prognosis in invasive disease and altered cell function in vitro. The results of this study suggest that heterozygosity for a germ-line mutation in BRCA1 or BRCA2 results in development of PRA predominance. This is likely to lead to changes in progesterone signaling in hormone-dependent tissues, which may be a factor in the increased risk of cancer in these tissues in women with germ-line BRCA1 or BRCA2 mutations.
Collapse
Affiliation(s)
- Patricia A Mote
- Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, Australia
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Callens N, Baert JL, Monté D, Sunesen M, Van Lint C, de Launoit Y. Transcriptional regulation of the murine brca2 gene by CREB/ATF transcription factors. Biochem Biophys Res Commun 2004; 312:702-7. [PMID: 14680822 DOI: 10.1016/j.bbrc.2003.10.176] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2003] [Indexed: 11/28/2022]
Abstract
The brca2 gene encodes a nuclear protein which is mainly involved in DNA repair and, when mutated, is responsible for some of the hereditary breast cancers. However, brca2 expression is also deregulated in sporadic breast tumors. In the mouse brca2 gene we had earlier identified a region of 148bp upstream of the transcription start site sufficient to activate its expression. In the present report, we show that the -92 to -40bp region is essential for the transcription of brca2 in murine mammary cells and that this nucleotide sequence contains one putative CREB/ATF consensus site (cAMP responsive element: CRE). We demonstrated that the mutation of this binding site led to a highly significant reduction of the mouse brca2 transcription, and that CREB, CREM, and/or ATF-1 functionally bound to and regulated this promoter. Therefore, the regulation of the promoter of the mouse brca2 gene is driven by this family of transcription factors.
Collapse
Affiliation(s)
- Nathalie Callens
- UMR 8117 CNRS, Institut Pasteur de Lille, Université de Lille 1, Institut de Biologie de Lille, BP 447, 1 rue Calmette, 59021 Lille Cedex, France
| | | | | | | | | | | |
Collapse
|
|
48
|
Vissac-Sabatier C, Bignon YJ, Bernard-Gallon DJ. Effects of the phytoestrogens genistein and daidzein on BRCA2 tumor suppressor gene expression in breast cell lines. Nutr Cancer 2004; 45:247-55. [PMID: 12881020 DOI: 10.1207/s15327914nc4502_15] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
A high intake of isoflavones is associated with a reduction of breast cancer among Japanese women. The aim of this study was to quantify BRCA2 tumor suppressor gene expression after treatment of cells with the phytoestrogens daidzein and genistein, the main compounds of soy. The effects of 5 microg/ml genistein and 20 microg/ml daidzein on BRCA2 expression were studied in two human mammary tumor cell lines, MCF7 and MDA-MB-231, and one normal human breast epithelial cell line, MCF10a. BRCA2 mRNA was evaluated by quantitative real time RT-PCR and the amount of BRCA2 protein was measured by affinity chromatography. With Genistein, we observed a 60% increase of BRCA2 mRNA in MDA-MB-231 and MCF10a, which are, respectively, estrogen receptors alpha-/beta+ and alpha-/beta-, and no variation in MCF7, which is ERalpha+/beta+. Dairzein had no effect on BRCA2 mRNA expression. The level of BRCA2 protein with both food components also remained unchanged in all three cell lines. This suggests regulation of BRCA2 between the mRNA and protein levels. Treatment with actinomycin D and cycloheximide demonstrated that the increase in BRCA2 mRNA was not blocked by cycloheximide, indicating that de novo protein synthesis was required in MDA-MB-23, although de novo synthesis was not required in MCF10a for the genistein. With actinomycin D, genistein had a positive effect on the transcriptional level of BRCA2 mRNA in MDA-MB-231 and MCF10a. The use of an anti-estrogen suggested that the action of daidzein and genistein might not be mediated through the ER.
Collapse
Affiliation(s)
- Cécile Vissac-Sabatier
- Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, UMR 484 INSERM-UdA, BP 392, 58 Rue Montalembert, 63011 Clermont-Ferrand Cedex 01, France
| | | | | |
Collapse
|
|
49
|
Xiong J, Fan S, Meng Q, Schramm L, Wang C, Bouzahza B, Zhou J, Zafonte B, Goldberg ID, Haddad BR, Pestell RG, Rosen EM. BRCA1 inhibition of telomerase activity in cultured cells. Mol Cell Biol 2003; 23:8668-90. [PMID: 14612409 PMCID: PMC262673 DOI: 10.1128/mcb.23.23.8668-8690.2003] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2003] [Revised: 07/10/2003] [Accepted: 08/15/2003] [Indexed: 11/20/2022] Open
Abstract
Telomerase, an enzyme that maintains telomere length, plays major roles in cellular immortalization and cancer progression. We found that an exogenous BRCA1 gene strongly inhibited telomerase enzymatic activity in human prostate and breast cancer cell lines and caused telomere shortening in cell lines expressing wild-type BRCA1 (wtBRCA1) but not a tumor-associated mutant BRCA1 (T300G). wtBRCA1 inhibited the expression of the catalytic subunit (telomerase reverse transcriptase [TERT]) but had no effect on the expression of a subset of other components of the telomerase holoenzyme or on the expression of c-Myc, a transcriptional activator of TERT. However, endogenous BRCA1 associated and partially colocalized with c-Myc; exogenous wtBRCA1 strongly suppressed TERT promoter activity in various cell lines. The TERT inhibition was due, in part, to suppression of c-Myc E-box-mediated transcriptional activity. Suppression of TERT promoter and c-Myc activity required the amino terminus of BRCA1 but not the carboxyl terminus. Finally, endogenous BRCA1 and c-Myc were detected on transfected mouse and human TERT promoter segments in vivo. We postulate that inhibition of telomerase may contribute to the BRCA1 tumor suppressor activity.
Collapse
Affiliation(s)
- Jingbo Xiong
- Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Abstract
Mutations of the breast cancer susceptibility gene BRCA1 are linked to hereditary early onset breast and breast-ovarian cancer syndromes. These mutations confer an increased risk for other hormone-dependent cancers, including those of the uterus, cervix and prostate. BRCA1 expression is decreased or absent in a significant proportion of sporadic breast and ovarian cancers, suggesting a wider role in these tumor types. Multiple functions for BRCA1 have been identified, including roles in DNA repair, cell-cycle progression and apoptosis. These functions are consistent with a tumor suppressor activity, but they do not explain why BRCA1 mutation carriers develop hormone-responsive cancer types. Recent studies indicate that BRCA1 interacts with and regulates the activity of estrogen receptor alpha (ER alpha) and the androgen receptor. Its expression is regulated by carcinogens and anticarcinogens that modulate ER alpha signaling, suggesting a molecular linkage between BRCA1 and hormone-responsive cancers.
Collapse
Affiliation(s)
- Eliot M Rosen
- Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, DC 20057, USA.
| | | | | | | |
Collapse
|