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Genetic Ablation of Caveolin-1 Drives Estrogen-Hypersensitivity and the Development of DCIS-Like Mammary Lesions

By Isabelle Mercier, Mathew C. Casimiro, Jie Zhou, Chenguang Wang, Christopher Plymire, Kelly G. Bryant, Kristin M. Daumer, Federica Sotgia, Gloria Bonuccelli, Agnieszka K. Witkiewicz, Justin Lin, Thai Hong Tran, Janet Milliman, Philippe G. Frank, Jean-François Jasmin, Hallgeir Rui, Richard G. Pestell and Michael P. Lisanti

Abstract

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-α. 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 β-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

Topics: Regular Articles
Publisher: American Society for Investigative Pathology
OAI identifier: oai:pubmedcentral.nih.gov:2671351
Provided by: PubMed Central
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