Faculty Collaboration Database

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. Am J Pathol 2006 Nov;169(5):1784-801

Date

10/31/2006

Pubmed ID

17071600

Pubmed Central ID

PMC1780215

DOI

10.2353/ajpath.2006.060590

Scopus ID

2-s2.0-33845312826 (requires institutional sign-in at Scopus site)   78 Citations

Abstract

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.

Author List

Williams TM, Sotgia F, Lee H, Hassan G, Di Vizio D, Bonuccelli G, Capozza F, Mercier I, Rui H, Pestell RG, Lisanti MP

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Animals
Caveolin 1
Cell Proliferation
Cyclin D1
Enzyme Activation
Epithelial Cells
Female
Hyperplasia
Male
Mammary Glands, Animal
Mammary Neoplasms, Animal
Mammary Tumor Virus, Mouse
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Phenotype
Protective Agents
STAT5 Transcription Factor
Signal Transduction
Stromal Cells