Survival signals in breast cancer cells mediated by Myc stabilization.
Item
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Title
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Survival signals in breast cancer cells mediated by Myc stabilization.
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Identifier
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AAI3231967
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identifier
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3231967
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Creator
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Rodrik-Outmezguine, Vanessa.
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Contributor
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Adviser: David A. Foster
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Date
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2006
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular
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Abstract
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Estrogens, which have been strongly implicated in the development of breast cancer, enhance proliferation of mammary epithelial cells and particularly of estrogen receptor (ER) positive breast cancer cells. In the absence of serum growth factors, the ER positive MCF-7 breast cancer cell line undergoes apoptosis. However, estrogens, most commonly 17-beta-estradiol (E2), can suppress apoptosis in MCF-7 cells deprived of serum. While E2 stimulates a short-term transient increase in Myc expression, E2 also stimulated a sustained increase in the expression of Myc that was detectable at 48 hr and pronounced at 5 days---the point where increased proliferation of MCF-7 cells in the absence of serum could be detected. The Myc-dependent survival signal generated by E2 at 5 days was in fact dependent upon basal levels of mammalian target of rapamycin (mTOR) and two upstream regulators of mTOR, phosphatidylinositol-3-kinase (PI3K) and phospholipase D (PLD). Phospholipase D (PLD), which is commonly elevated in ER negative breast cancer cells, also suppresses apoptosis in breast cancer cells. We thus hypothesized that during breast cancer progression when the ER positive breast cancer cells lose their estrogen receptor and become ER negative cells, elevated PLD activity promotes cell survival overcoming the loss of estrogen dependence. Myc expression, which is elevated in a significant percentage of human cancers, is regulated at many different levels, including transcription, translation, as well as post-translationally. We report here that the sustained long-term elevation of Myc expression in response to both E2 and PLD is due to reduced turnover of Myc protein. The stabilization of Myc in response to E2 and PLD is due primarily to suppression of phosphorylation of Myc at Thr58 by glycogen synthase kinase-3beta (GSK-3beta). Consistent with previous reports demonstrating that phosphorylation of Myc at Thr58 targets Myc for ubiquitination and degradation by the proteasome, both E2 and PLD suppressed ubiquitination of Myc. The ability of both estrogen and PLD to suppress phosphorylation of Myc at Thr58, which promotes Myc stabilization, is likely a critical aspect of the survival signals generated by E2 and PLD in hormone-dependent and hormone-independent breast cancer and will be discussed in this work.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
