Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer

PLoS Biol. 2011 Nov;9(11):e1001199. doi: 10.1371/journal.pbio.1001199. Epub 2011 Nov 15.

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 ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aurora Kinase A
  • Aurora Kinases
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Breast / cytology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Polarity* / genetics
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genotype
  • HeLa Cells
  • Heterozygote
  • Humans
  • Hyaluronan Receptors / genetics*
  • Hyaluronan Receptors / metabolism*
  • Microtubules / physiology
  • Microtubules / ultrastructure
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Estrogen / analysis

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • Receptors, Estrogen
  • hyaluronan-mediated motility receptor
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases