About 10% of breast cancers are due to mutations in genes called BRCA1 and BRCA2. However, the molecular mechanism by which alteration of these genes greatly increases the risk of cancer is not fully understood. In a new study, published Nov. 15 in the online, open-access journal PLoS Biology, an international team led by Miquel Àngel Pujana, of Bellvitge Biomedical Research Institute (IDIBELL) and the Catalan Institute of Oncology (ICO), and Christopher Maxwell, now at the Child and Family Research Institute, has made an important step towards revealing the underlying pathways.
The researchers found a key interaction between BRCA1 and another protein called RHAMM (encoded by the HMMR gene). These two proteins act on a previously unknown molecular mechanism that regulates epithelial cell polarity. The researchers have shown that BRCA1 and RHAMM control the normal development of breast epithelial cells. If one or both of these genes have mutations, then the normal architecture and development of breast cells is altered in ways that increase the risk of a specific tumor type appearing.
"BRCA1 mutation carriers are at high risk for breast cancer," said Pujana, "but these mutations exhibit variable penetrance, which can be in part explained by other genetic factors such as the identified variant in HMMR." A common genetic variant of HMMR slightly increases (approximately 1.1-fold) the risk of breast cancer in women carrying BRCA1 mutations. "Therefore, by itself, this variant does not justify a genetic analysis," explains Pujana.
But as shown by other CIMBA (Consortium of Investigators of Modifiers of BRCA1 and BRCA2) investigators, if other mutations are added which also slightly modify the risk -- and about twenty are known now -- then "it may vary considerably the risk of developing breast cancer in these women. Depending on the combination of genetic modifier variants that are inherited, the risk of developing cancer might be increased or decreased. " The researchers initially discovered the effect of HMMR by genetic analysis of affected families. Then they went on to analyse the roles of these genes in breast cells and their effects when mutated or functionally perturbed. They found that RHAMM and BRCA1 interact with proteins known to control key aspects of cell polarity and the cell division cycle, perhaps explaining why certain types of breast cancer have characteristic cell morphology and cell proliferation characteristics.
The investigation of these genetic variants is directed towards developing more accurate genetic models that can predict the risk of cancer in women who carry BRCA1 or BRCA2 mutations, and thus to help them to take appropriate preventive measures. Variants are also associated with different types of tumors, with important implications for patient prognosis.
Funding: This work was funded by the Spanish Ministries of Health, and Science and Innovation (CB07/02/2005; FIS 08/1120, 08/1359, 08/1635, and 09/02483; RTICCC RD06/0020/1060 and RD06/0020/0028; Transversal Action Against Cancer; the Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases; and the "Ramón y Cajal" Young Investigator Program), the Spanish National Society of Medical Oncology (2010), the Spanish Association Against Cancer (AECC 2010), the AGAUR Catalan Government Agency (2009SGR1489 and 2009SGR293; and the Beatriu Pinós Postdoctoral Program), the Ramón Areces Foundation (XV), the "Roses Contra el Càncer" Foundation, the Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK (C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, and C8197/A10123), the National Institute for Health Research (UK), the Association for International Cancer Research (AICR-07-0454), the Ligue National Contre le Cancer (France), the Association "Le cancer du sein, parlons-en!", the Dutch Cancer Society (NKI 1998-1854, 2004-3088, and 2007-3756), the Fondazione Italiana per la Ricerca sul Cancro ("Hereditary Tumors"), the Associazione Italiana per la Ricerca sul Cancro (4017), the Italian Ministero della Salute (RFPS-2006-3-340203 and "Progetto Tumori Femminili"), the Italian Ministero dell'Universita' e Ricerca (RBLAO3-BETH), the Fondazione IRCCS Istituto Nazionale Tumori (INT "5x1000"), the Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori), the National Breast Cancer Foundation (Australia), the Australian National Health and Medical Research Council (145684, 288704, and 454508), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, the Cancer Foundation of Western Australia, the German Cancer Aid (107054), the Center for Molecular Medicine Cologne (TV93), the National Cancer Institute (USA; CA128978 and CA122340), National Institutes of Health (RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, and CA69638), the Research Triangle Institute Informatics Support Center (RFP N02PC45022-46), the Specialized Program of Research Excellence (SPORE P50 CA83638 and CA113916), the Department of Defense Breast Cancer Research Program (05/0612), the Eileen Stein Jacoby Fund, the Breast Cancer Research Foundation, the Marianne and Robert MacDonald Foundation, the Komen Foundation, the Helsinki University Central Hospital Research Fund, the Academy of Finland (110663), the Finnish Cancer Society, the Sigrid Juselius Foundation, and the EU FP7 (223175, HEALTH-F2-2009-223175). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Citation: Maxwell CA, Benìtez J, Gòmez-Baldò L, Osorio A, Bonifaci N, et al. (2011) Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer. PLoS Biol 9(11): e1001199. doi:10.1371/journal.pbio.1001199