title: 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.
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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Hyangkyu
authors.initials: H
authors.lastname: Lee
authors.forename: Ghada
authors.initials: G
authors.lastname: Hassan
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Franco
authors.initials: F
authors.lastname: Capozza
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: 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*
chemical_list: 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