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(American Journal of Pathology. 2009;174:1172-1190.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080882

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

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

From the Kimmel Cancer Center,* Departments of Cancer Biology and Medical Oncology, Thomas Jefferson, University, Philadelphia, Pennsylvania; the Stem Cell Biology and Regenerative Medicine Center,{dagger} Thomas Jefferson University, Philadelphia, Pennsylvania; the Muscular and Neurodegenerative Disease Unit,{ddagger} University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy; and the Department of Pathology,§ Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

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 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.




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L. A. Emery, A. Tripathi, C. King, M. Kavanah, J. Mendez, M. D. Stone, A. de las Morenas, P. Sebastiani, and C. L. Rosenberg
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[Abstract] [Full Text] [PDF]


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