title: Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Bluemle Life Sciences Building, Room 933, 233 S. 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Magalis A
authors.initials: MA
authors.lastname: Vuolo
authors.forename: Maomi
authors.initials: M
authors.lastname: Li
authors.forename: Wan Cai
authors.initials: WC
authors.lastname: Yang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D051242:Caveolin 1 / Q000235:genetics* / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D051242:Caveolin 1; D047628:Estrogen Receptor alpha; D019938:Cyclin D1