| 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-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. |
| Authors | 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
(Affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.)
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| Journal | The American journal of pathology
(Am J Pathol)
Vol. 174
Issue 4
Pg. 1172-90
(Apr 2009)
ISSN: 1525-2191 [Electronic] United States |
| PMID | 19342371
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
|
| Chemical References |
- Caveolin 1
- Estrogen Receptor alpha
- Estrogens
- Foxa1 protein, mouse
- Hepatocyte Nuclear Factor 3-alpha
- RNA-Binding Proteins
- Receptors, Progesterone
- Rnpc2 protein, mouse
- Trans-Activators
|
| Topics |
- Animals
- Carcinoma, Intraductal, Noninfiltrating
(genetics, metabolism, pathology)
- Caveolin 1
(deficiency, genetics)
- Cell Transformation, Neoplastic
(genetics)
- Estrogen Receptor alpha
(genetics, metabolism)
- Estrogens
(pharmacology)
- Female
- Gene Expression Profiling
- Hepatocyte Nuclear Factor 3-alpha
(genetics, metabolism)
- Humans
- Immunohistochemistry
- Mammary Neoplasms, Experimental
(genetics, metabolism, pathology)
- Mice
- Mice, Knockout
- Oligonucleotide Array Sequence Analysis
- Ovariectomy
- RNA-Binding Proteins
(genetics, metabolism)
- Receptors, Progesterone
(genetics, metabolism)
- Tissue Array Analysis
- Trans-Activators
(genetics, metabolism)
|
