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 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.
Williams
Terence M
TM
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Sotgia
Federica
F
Lee
Hyangkyu
H
Hassan
Ghada
G
Di Vizio
Dolores
D
Bonuccelli
Gloria
G
Capozza
Franco
F
Mercier
Isabelle
I
Rui
Hallgeir
H
Pestell
Richard G
RG
Lisanti
Michael P
MP
D000273:Adipose Tissue / Q000166:cytology / Q000473:pathology; D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency / Q000378:metabolism*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D006965:Hyperplasia; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010641:Phenotype; D020011:Protective Agents / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology*
D051242:Caveolin 1; D020011:Protective Agents; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D019938:Cyclin D1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3