Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions

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, Michael P. Lisanti

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44 Scopus citations

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 Foxal, 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-relatedgenes 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.

Original languageEnglish (US)
Pages (from-to)1172-1190
Number of pages19
JournalAmerican Journal of Pathology
Volume174
Issue number4
DOIs
Publication statusPublished - Apr 2009

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Mercier, I., Casimiro, M. C., Zhou, J., Wang, C., Plymire, C., Bryant, K. G., ... Lisanti, M. P. (2009). Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions. American Journal of Pathology, 174(4), 1172-1190. https://doi.org/10.2353/ajpath.2009.080882