Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions. Am J Pathol 2009 Apr;174(4):1172-90
Date
04/04/2009Pubmed ID
19342371Pubmed Central ID
PMC2671351DOI
10.2353/ajpath.2009.080882Scopus ID
2-s2.0-65349132368 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
Caveolin-1 (Cav-1) loss-of-function mutations are exclusively associated with estrogen receptor-positive (ER(+)) human breast cancers. To dissect the role of Cav-1 loss-of-function in the pathogenesis of human breast cancers, we used Cav-1(-/-) null mice as a model system. First, we demonstrated that Cav-1(-/-) mammary epithelia overexpress two well-established ER co-activator genes, CAPER and Foxa1, in addition to ER-alpha. Thus, the functional loss of Cav-1 may be sufficient to confer estrogen-hypersensitivity in the mammary gland. To test this hypothesis directly, we subjected Cav-1(-/-) mice to ovariectomy and estrogen supplementation. As predicted, Cav-1(-/-) mammary glands were hyper-responsive to estrogen and developed dysplastic mammary lesions with adjacent stromal angiogenesis that resemble human ductal carcinoma in situ. Based on an extensive biomarker analysis, these Cav-1(-/-) mammary lesions contain cells that are hyperproliferative and stain positively with nucleolar (B23/nucleophosmin) and stem/progenitor cell markers (SPRR1A and beta-catenin). Genome-wide transcriptional profiling identified many estrogen-related genes that were over-expressed in Cav-1(-/-) mammary glands, including CAPER--an ER co-activator gene and putative stem/progenitor cell marker. Analysis of human breast cancer samples revealed that CAPER is overexpressed and undergoes a cytoplasmic-to-nuclear shift during the transition from pre-malignancy to ductal carcinoma in situ. Thus, Cav-1(-/-) null mice are a new preclinical model for studying the molecular paradigm of estrogen hypersensitivity and the development of estrogen-dependent ductal carcinoma in situ lesions.
Author List
Mercier I, Casimiro MC, Zhou J, Wang C, Plymire C, Bryant KG, Daumer KM, Sotgia F, Bonuccelli G, Witkiewicz AK, Lin J, Tran TH, Milliman J, Frank PG, Jasmin JF, Rui H, Pestell RG, Lisanti MPMESH terms used to index this publication - Major topics in bold
AnimalsCarcinoma, Intraductal, Noninfiltrating
Caveolin 1
Cell Transformation, Neoplastic
Estrogen Receptor alpha
Estrogens
Female
Gene Expression Profiling
Hepatocyte Nuclear Factor 3-alpha
Humans
Immunohistochemistry
Mammary Neoplasms, Experimental
Mice
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Ovariectomy
RNA-Binding Proteins
Receptors, Progesterone
Tissue Array Analysis
Trans-Activators