Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status

Am J Pathol. 2006 Jun;168(6):1998-2013. doi: 10.2353/ajpath.2006.051089.


A Japanese study reported that up to 16% of breast cancer samples harbor a sporadic mutation within the human Cav-1 gene, namely P132L. To date, however, no studies have examined the United States' population. Here, we developed a novel allele-specific real-time PCR assay to detect the Cav-1 P132L mutation in mammary tumor cells isolated by laser capture microdissection from formalin-fixed paraffin-embedded breast cancer samples. We report that the Cav-1 P132L mutation is present in approximately 19% of estrogen receptor alpha (ERalpha)-positive breast cancers but not in ERalpha-negative breast cancers. This is the first demonstration that the P132L mutation is exclusively associated with ERalpha-positive mammary tumors. We also identified six novel Cav-1 mutations associated with ERalpha-positive breast cancers (W128Stop, Y118H, S136R, I141T, Y148H, and Y148S). Thus, the overall incidence of Cav-1 mutations in ERalpha-positive breast cancers approaches 35% (greater than one-third). To mechanistically dissect the functional relationship between Cav-1 gene inactivation and ERalpha expression, we isolated primary mammary epithelial cells from wild-type and Cav-1-/- mice and cultured them in a three-dimensional system, allowing them to form mammary acinar-like structures. Under conditions of growth factor deprivation, Cav-1-deficient mammary acini displayed increased ERalpha levels and enhanced sensitivity toward estrogen-stimulated growth, with specific up-regulation of cyclin D1. Finally, we discuss the possibility that sporadic Cav-1 mutations may act as an initiating event in human breast cancer pathogenesis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms / genetics*
  • Caveolin 1 / genetics*
  • Caveolin 1 / physiology*
  • Cyclin D1 / genetics*
  • Estrogen Receptor alpha / genetics*
  • Female
  • Humans
  • Mammary Neoplasms, Animal / genetics*
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation*
  • Polymorphism, Single Nucleotide


  • Caveolin 1
  • Estrogen Receptor alpha
  • Cyclin D1