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(American Journal of Pathology. 2006;169:1784-1801.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060590

Stromal and Epithelial Caveolin-1 Both Confer a Protective Effect Against Mammary Hyperplasia and Tumorigenesis

Caveolin-1 Antagonizes Cyclin D1 Function in Mammary Epithelial Cells

Terence M. Williams*, Federica Sotgia*{dagger}, Hyangkyu Lee*, Ghada Hassan*, Dolores Di Vizio{ddagger}, Gloria Bonuccelli*, Franco Capozza*, Isabelle Mercier*, Hallgeir Rui*, Richard G. Pestell* and Michael P. Lisanti*{dagger}

From the Department of Cancer Biology,* Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; the John F. Enders Research Laboratories,{ddagger} Children’s Hospital, Harvard Medical School, Boston, Massachusetts; and the Muscular and Neurodegenerative Disease Unit,{dagger} University of Genova and G. Gaslini Pediatric Institute, Genova, Italy

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 bromodeoxyuridine 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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