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.
| Original language | English |
|---|---|
| Pages (from-to) | 1784-1801 |
| Number of pages | 18 |
| Journal | American Journal of Pathology |
| Volume | 169 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2006 Nov |
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All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
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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. / 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.
In: American Journal of Pathology, Vol. 169, No. 5, 11.2006, p. 1784-1801.Research output: Contribution to journal › Article
TY - JOUR
T1 - Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis
T2 - Caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells
AU - Williams, Terence M.
AU - Sotgia, Federica
AU - Lee, Hyangkyu
AU - Hassan, Ghada
AU - Di Vizio, Dolores
AU - Bonuccelli, Gloria
AU - Capozza, Franco
AU - Mercier, Isabelle
AU - Rui, Hallgeir
AU - Pestell, Richard G.
AU - Lisanti, Michael P.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33845312826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845312826&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2006.060590
DO - 10.2353/ajpath.2006.060590
M3 - Article
C2 - 17071600
AN - SCOPUS:33845312826
VL - 169
SP - 1784
EP - 1801
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 5
ER -