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

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 Ca...

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Published in:The American journal of pathology Vol. 169; no. 5; p. 1784
Main Authors: Williams, Terence M, Sotgia, Federica, Lee, Hyangkyu, Hassan, Ghada, Di Vizio, Dolores, Bonuccelli, Gloria, Capozza, Franco, Mercier, Isabelle, Rui, Hallgeir, Pestell, Richard G, Lisanti, Michael P
Format: Journal Article
Language:English
Published: United States 01.11.2006
Subjects:
Adipose Tissue - cytology
Adipose Tissue - pathology
Animals
Caveolin 1 - deficiency
Caveolin 1 - metabolism
Cell Proliferation
Cyclin D1 - antagonists & inhibitors
Cyclin D1 - metabolism
Enzyme Activation
Epithelial Cells - cytology
Female
Hyperplasia
Male
Mammary Glands, Animal - pathology
Mammary Neoplasms, Animal - chemically induced
Mammary Neoplasms, Animal - pathology
Mammary Tumor Virus, Mouse
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Phenotype
Protective Agents - metabolism
Signal Transduction
STAT5 Transcription Factor - metabolism
Stromal Cells - cytology
ISSN:0002-9440
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Summary: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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ISSN:0002-9440
DOI:10.2353/ajpath.2006.060590