Journal
PLOS BIOLOGY
Volume 9, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.1001199
Keywords
-
Categories
Funding
- Spanish Ministries of Health, and Science ane Innovation [CB07/02/2005]
- FIS [08/1120, 08/1359, 08/1635, 09/02483]
- RTICCC [RD06/0020/1060, RD06/0020/0028]
- Transversal Action Against Cancer
- Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases
- Ramon y Cajal Young Investigator Program
- Spanish National Society of Medical Oncology
- Spanish Association Against Cancer [AECC 2010]
- AGAUR Catalan Government Agency [2009SGR1489, 2009SGR293]
- Beatriu Pinos Postdoctoral Program
- Ramon Areces Foundation
- Roses Contra el Cancer Foundation
- Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK [C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, C8197/A10123]
- National Institute for Health Research (UK)
- Association for International Cancer Research [AICR-07-0454]
- Ligue National Contre le Cancer (France)
- Association Le cancer du sein, parlons-en!
- Dutch Cancer Society [NKI 1998-1854, 2004-3088, 2007-3756]
- Fondazione Italiana per la Ricerca sul Cancro (Hereditary Tumors)
- Associazione Italiana per la Ricerca sul Cancro [4017]
- Italian Ministero della Salute [RFPS-2006-3-340203]
- Italian Ministero dell'Universita e Ricerca [RBLAO3-BETH]
- Fondazione IRCCS Istituto Nazionale Tumori [INT 5x1000]
- Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori)
- National Breast Cancer Foundation (Australia)
- Australian National Health and Medical Research Council [145684, 288704, 454508]
- Queensland Cancer Fund
- Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia
- Cancer Foundation of Western Australia
- German Cancer Aid [107054]
- Center for Molecular Medicine Cologne [TV93]
- National Cancer Institute (USA) [CA128978, CA122340]
- National Institutes of Health [RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, CA69638]
- Research Triangle Institute Informatics Support Center [RFP N02PC45022-46]
- Specialized Program of Research Excellence (SPORE) [P50 CA83638, CA113916]
- Department of Defense [05/0612]
- Eileen Stein Jacoby Fund
- Breast Cancer Research Foundation
- Marianne and Robert MacDonald Foundation
- Komen Foundation
- Helsinki University Central Hospital
- Academy of Finland [110663]
- Finnish Cancer Society
- Sigrid Juselius Foundation
- EU [223175, HEALTH-F2-2009-223175]
- Cancer Research UK [10118, 11022, 11174] Funding Source: researchfish
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Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (wHR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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