Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast / drug effects
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / chemically induced
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Caveolin 1
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Caveolins / antagonists & inhibitors
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Caveolins / biosynthesis
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Caveolins / deficiency*
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Caveolins / genetics
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Down-Regulation
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Estradiol / pharmacology
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Estrogen Receptor alpha / biosynthesis*
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Estrogen Receptor alpha / genetics
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Female
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Humans
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Mammary Neoplasms, Experimental / chemically induced
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Nude
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beta-Cyclodextrins / pharmacology
Substances
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CAV1 protein, human
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Cav1 protein, mouse
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Caveolin 1
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Caveolins
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Estrogen Receptor alpha
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beta-Cyclodextrins
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methyl-beta-cyclodextrin
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Estradiol