TY - JOUR
T1 - Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions
AU - Mercier, Isabelle
AU - Casimiro, Mathew C.
AU - Zhou, Jie
AU - Wang, Chenguang
AU - Plymire, Christopher
AU - Bryant, Kelly G.
AU - Daumer, Kristin M.
AU - Sotgia, Federica
AU - Bonuccelli, Gloria
AU - Witkiewicz, Agnieszka K.
AU - Lin, Justin
AU - Tran, Thai Hong
AU - Milliman, Janet
AU - Frank, Philippe G.
AU - Jasmin, Jean François
AU - Rui, Hallgeir
AU - Pestell, Richard G.
AU - Lisanti, Michael P.
N1 - Funding Information:
Supported by grants from the NIH/NCI ( R01-CA-80250; R01-CA-098779; R01-CA-120876 ), the American Association for Cancer Research (AACR), and the Department of Defense-Breast Cancer Research Program (Synergistic Idea Award) to M.P.L.; a Post-doctoral Fellowship from the Susan G. Komen Breast Cancer Foundation to I.M.; grants from the Elsa U. Pardee Foundation, the W.W. Smith Charitable Trust, and a Research Scholar Grant from the American Cancer Society (ACS) to F.S.; a Career Catalyst Award from the Susan G. Komen Breast Cancer Foundation to J.F.J., and a grant with the Pennsylvania Department of Health (to M.P.L.), which specifically disclaims responsibility for any analyses, interpretations or conclusions. R.G.P. was supported by grants from the NIH/NCI ( R01-CA-70896, R01-CA-75503, R01-CA-86072, and R01-CA-107382 ) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.).
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2009.080882
DO - 10.2353/ajpath.2009.080882
M3 - Article
C2 - 19342371
AN - SCOPUS:65349132368
SN - 0002-9440
VL - 174
SP - 1172
EP - 1190
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -