Caveolin-1 down-regulation activates estrogen receptor alpha expression and leads to 17beta-estradiol-stimulated mammary tumorigenesis.
Constitutive activation of estrogen receptor alpha (ER-alpha) expression is an early event in breast cancer tumorigenesis. However, the mechanism whereby ER-alpha is constitutively activated during transformation of normal mammary cells has not been well established. Previously, we reported that haploinsufficiency of caveolin-1, a major structural protein that forms caveolae, resulted in anchorage-independent growth of a normal mammary epithelial cell line, MCF10A. Here, we further demonstrated that ER-alpha but not ER-beta expression was constitutively activated in these caveolin-1 haploinsufficient cells. Transient treatment of MCF10A cells with beta-methyl-cyclodextrin, a chemical that can displace caveolin-1 from the plasma membrane, also stimulated ER-alpha expression. We further found that the 17beta-estradiol (E2) accelerated anchorage-independent growth of these cells in vitro and promoted their tumorigenesis in nude mice. These results suggest that dysregulation of caveolin-1 is one of the mechanisms by which ER-alpha expression is activated during initiation of breast tumorigenesis.
Zhang
Xintian
X
Cancer Center, Creighton University, Omaha, NE 68178, USA.
Shen
Peng
P
Coleman
Megan
M
Zou
Wei
W
Loggie
Brian W
BW
Smith
Leia M
LM
Wang
Zhaoyi
Z
D000818:Animals; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D047392:beta-Cyclodextrins / Q000494:pharmacology
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D047628:Estrogen Receptor alpha; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D004958:Estradiol