TITLE

Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

AUTHOR(S)
Maxwell, Christopher A.; Benítez, Javier; Gómez-Baldó, Laia; Osorio, Ana; Bonifaci, Nú ria; Fernández-Ramires, Ricardo; Costes, Sylvain V.; Guinó, Elisabet; Chen, Helen; Evans, Gareth J. R.; Mohan, Pooja; Català, Isabel; Petit, Anna; Aguilar, Helena; Villanueva, Alberto; Aytes, Alvaro; Serra-Musach, Jordi; Rennert, Gad; Lejbkowicz, Flavio; Peterlongo, Paolo
PUB. DATE
November 2011
SOURCE
PLoS Biology;Nov2011, Vol. 9 Issue 11, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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), ρtrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94-1.16), ρtrend = 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.
ACCESSION #
75606806

 

Related Articles

  • Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers. Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva // PLoS ONE;Apr2015, Vol. 10 Issue 4, p1 

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between...

  • Apico-basal polarity complex and cancer. Khursheed, Mohammed; Bashyam, Murali // Journal of Biosciences;Mar2014, Vol. 39 Issue 1, p145 

    Apico-basal polarity is a cardinal molecular feature of adult eukaryotic epithelial cells and appears to be involved in several key cellular processes including polarized cell migration and maintenance of tissue architecture. Epithelial cell polarity is maintained by three well-conserved...

  • Pregnancies, Breast-Feeding, and Breast Cancer Risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). Andrieu, Nadine; Goldgar, David E.; Easton, Douglas F.; Rookus, Matti; Brohet, Richard; Antoniou, Antonis C.; Peock, Susan; Evans, Gareth; Eccles, Diana; Douglas, Fiona; Noguës, Catherine; Gauthier-Villars, Marion; Chompret, Agnes; Leeuwen, Flora E. Van; Kluijt, Irma; Benitez, Javier; Arver, Brita; Olah, Edith; Chang-Claude, Jenny // JNCI: Journal of the National Cancer Institute;4/19/2006, Vol. 98 Issue 8, p535 

    Background: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate...

  • BRCA 1 and BRCA 2. Peters, Michael // BMA A-Z Family Medical Encyclopedia;2004, p123 

    An encyclopedia entry for "BRCA 1 and BRCA 2" is presented. It refers to two of the abnormal genes that are speculated to be responsible for inherited breast cancer. Women with BRCA 1 and BRCA 2 genes may experience an increased risk of ovarian cancer.

  • A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Antoniou, A.C.; Pharaoh, P.D.P.; McMullan, G.; Day, N.E.; Stratton, M.R.; Peto, J.; Ponder, B.J.; Easton, D.F.; Pharoah, P D P // British Journal of Cancer;1/7/2002, Vol. 86 Issue 1, p76 

    In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in...

  • Breast Cancer.  // Annals of Internal Medicine;4/6/2004, Vol. 140 Issue 7, p543 

    Presents an update on the reduction in the risk of gynecologic and breast cancer by bilateral prophylactic oophorectomy. Study of the incidence of breast and ovarian cancer due to BRCA1 and BRCA2 genetic mutations and the effectiveness of prophylactic oophorectomy; Analysis of the data for...

  • A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers. Guinan, Emer M; Hussey, Juliette; McGarrigle, Sarah A; Healy, Laura A; O'Sullivan, Jacintha N; Bennett, Kathleen; Connolly, Elizabeth M // BMC Cancer;2013, Vol. 13 Issue 1, p1 

    Background: Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer...

  • Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status. Figueiredo, Jane; Brooks, Jennifer; Conti, David; Poynter, Jenny; Teraoka, Sharon; Malone, Kathleen; Bernstein, Leslie; Lee, Won; Duggan, David; Siniard, Ashley; Concannon, Patrick; Capanu, Marinela; Lynch, Charles; Olsen, J�rgen; Haile, Robert; Bernstein, Jonine // Breast Cancer Research & Treatment;Jul2011, Vol. 127 Issue 3, p819 

    Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous...

  • BRCA1 functions as a breast stem cell regulator. Foulkes, W.D. // Journal of Medical Genetics;Jan2004, Vol. 41 Issue 1, p1 

    BRCA1 is an important susceptibility gene for breast cancer, which confers substantial lifetime risks of breast cancer, particularly in the pre-menopausal age group. Typically, carriers of BRCA1 mutations develop breast tumours that grow rapidly and are high grade and oestrogen receptor...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics