Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 169, Issue 5, Pages 1784-1801Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2006.060590
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Funding
- NCI NIH HHS [R01 CA080250, R01CA98779, R01 CA093596, R01 CA098779, R01CA93596, R01CA80250] Funding Source: Medline
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Here, we investigate the role of caveolin-1 (Cav-1) in breast cancer onset and progression, with a focus on epithelial-stromal interactions, ie, the tumor microenvironment. Cav-1 is highly expressed in adipocytes and is abundant in mammary fat pads (stroma), but it remains unknown whether loss of Cav-1 within mammary stromal cells affects the differentiated state of mammary epithelia via paracrine signaling. To address this issue, we characterized the development of the mammary ductal system in Cav-1(-/-) mice and performed a series of mammary transplant studies, using both wild-type and Cav-1(-/-) mammary fat pads. Cav-1(-/-) mammary epithelia were hyperproliferative in vivo, with dramatic increases in terminal end bud area and mammary ductal thickness as well as increases in bromodeox-yuridine incorporation, extracellular signal-regulated kinase-1/2 hyperactivation, and up-regulation of STAT5a and cyclin D1. Consistent with these findings, loss of Cav-1 dramatically exacerbated mammary lobulo-alveolar hyperplasia in cyclin D1 Tg mice, whereas overexpression of Cav-1 caused reversion of this phenotype. Most importantly, Cav-1(-/-) mammary stromal cells (fat pads) promoted the growth of both normal mammary ductal epithelia and mammary tumor cells. Thus, Cav-1 expression in both epithelial and stromal cells provides a protective effect against mammary hyperplasia as well as mammary tumorigenesis.
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