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From the Department of Oncology,* Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; the Departments of Molecular Pharmacology and Medicine, Albert Einstein College of Medicine, Bronx, New York; the Muscular and Neurodegenerative Disease Unit, University of Genova and G.Gaslini Pediatric Institute, Genova, Italy; the Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; the Department of Pathology,¶ Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and the Albert Einstein Cancer Center, || Bronx, New York, New York
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 
19% of estrogen receptor (ER)-positive breast cancers but not in ER-negative breast cancers. This is the first demonstration that the P132L mutation is exclusively associated with ER-positive mammary tumors. We also identified six novel Cav-1 mutations associated with ER-positive breast cancers (W128Stop, Y118H, S136R, I141T, Y148H, and Y148S). Thus, the overall incidence of Cav-1 mutations in ER-positive breast cancers approaches 35% (greater than one-third). To mechanistically dissect the functional relationship between Cav-1 gene inactivation and ER 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 ER 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.
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