Hypoxia induces proteasome-dependent degradation of estrogen receptor a in ZR-75 breast cancer cells

Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466, USA.
Molecular Endocrinology (Impact Factor: 4.2). 11/2002; 16(10):2231-42. DOI: 10.1210/me.2001-0347
Source: PubMed

ABSTRACT Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.

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    • "Interestingly, ERa expression is repressed by hypoxia due to the induction of proteasomal degradation of the receptor (Cooper et al., 2004; Kurebayashi, Otsuki, Moriya, & Sonoo, 2001; Stoner et al., 2002). HIF- 1a is involved in this mechanism, but it is not yet clear how this effect is mediated. "
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    ABSTRACT: Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression.
    Vitamins & Hormones 01/2013; 93C:135-160. DOI:10.1016/B978-0-12-416673-8.00004-6 · 1.78 Impact Factor
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    • "A large body of data has shown that ER expression characterizes the evolution of low-and high-grade invasive breast carcinomas: while in the former it represents one of the main markers, in the latter ER is usually no longer expressed (Simpson et al., 2005). Whether ER loss is due to a selection of ER-negative tumor cell clones from a heterogeneous population of cells, or to a reduced ER expression/increased ER degradation in initially ER-positive cells, is currently unknown (Ottaviano et al., 1994; Massarweh et al., 2006; Sonoo et al., 1999; Stoner et al., 2002). In this context, E3 might exert differential activity on the basis of ER status and E2 availability since it exerts agonistic activity if used alone as well as antiestrogenic effects in the presence of E2 (Melamed et al., 1997; Lippman et al., 1977). "
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    ABSTRACT: Estrogens are structurally related steroids that regulate important physiological processes. 17beta-estradiol (E2) is reversibly oxidized to estrone (E1) and both E2 and E1 can be irreversibly converted to estriol (E3), which also originates directly from androstenedione. The action of E2 has been traditionally explained by the binding to the estrogen receptor (ER) alpha and ER beta, however the G protein-coupled receptor (GPR) 30 has been recently involved in the rapid signaling triggered by estrogens. Although the role of E2 in the development of breast cancer has been largely documented, the contribution of E3 still remains to be completely evaluated. Here, we demonstrate for the first time that E3 acts as a GPR30 antagonist since it was able to inhibit the GPR30-mediated responses such as the rapid ERK activation, the up-regulation of target genes like c-fos and connective tissue growth factor, the proliferative effects observed in ER-negative SkBr3 cells.
    Molecular and Cellular Endocrinology 02/2010; 320(1-2):162-70. DOI:10.1016/j.mce.2010.02.006 · 4.24 Impact Factor
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    • "M Dadiani, D Seger et al.: Estrogen regulation of VEGF in breast cancer of c-Myc by Tet; but due to experimental variations, the moderate long-term E 2 induction of c-Myc under normoxic conditions (1.5-fold as shown in Fig. 4B) was not significant in this particular set of experiments (Fig. 5B). However, hypoxia did reduce ERa level in cells cultivated in EWD and Tet medium, as well as in cells treated in E 2 medium (Fig. 5C), in accord with the finding of Stoner et al. (2002). Overall, we showed that hypoxic conditions induces VEGF mRNA expression more than 2-fold above the level induced by long-term E 2 treatment under normoxic conditions, dominating the expression level of VEGF. "
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    ABSTRACT: The role of c-Myc in estrogen regulation of vascular endothelial growth factor (VEGF) and of the vasculature function has been investigated in breast cancer cells and tumors. The studies were performed on MCF7 wild-type cells and MCF7-35im clone, stably transfected with an inducible c-Myc gene. In vitro and ex vivo methods for investigating molecular events were integrated with in vivo magnetic resonance imaging of the vascular function. The results showed that the c-Myc upregulation by estrogen is necessary for the transient induction of VEGF transcription; however, overexpression of c-Myc alone is not sufficient for this induction. Furthermore, both c-Myc and the activated estrogen receptor alpha (ERalpha) were shown to co-bind the VEGF promoter in close proximity, indicating a novel mechanism for estrogen regulation of VEGF. Studies of long-term estrogen treatment and overexpression of c-Myc alone demonstrated regulation of stable VEGF expression levels in vitro and in vivo, maintaining steady vascular permeability in tumors. However, withdrawal of estrogen from the tumors resulted in increased VEGF and elevated vascular permeability, presumably due to hypoxic conditions that were found to dominate VEGF overexpression in cultured cells. This work revealed a cooperative role for ERalpha and c-Myc in estrogen regulation of VEGF and the ability of c-Myc to partially mimic estrogen regulation of angiogenesis. It also illuminated the differences in estrogen regulation of VEGF during transient and long-term sustained treatments and under different microenvironmental conditions, providing a complementary picture of the in vitro and in vivo results.
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