Hypoxia Induces Proteasome-Dependent Degradation of Estrogen Receptor α in ZR-75 Breast Cancer Cells

Stoner, Michael W.; Saville, Bradley; Wormke, Mark; Dean, Dana D.; Burghardt, Robert C.; Safe, Stephen

doi:10.1210/me.2001-0347

Cited by 101 publications

(76 citation statements)

References 56 publications

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“…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).…”

Section: Dadiani D Seger Et Al: Estrogen Regulation Of Vegf In Brsupporting

confidence: 86%

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

Dadiani¹,

Seger²,

Kreizman³

et al. 2009

Endocrine-Related Cancer

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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 a (ERa) 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 ERa 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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“…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).…”

Section: Dadiani D Seger Et Al: Estrogen Regulation Of Vegf In Brsupporting

confidence: 86%

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

Dadiani¹,

Seger²,

Kreizman³

et al. 2009

Endocrine-Related Cancer

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“…3C) and hypoxia-induced inhibition of Ah-responsiveness was observed in cells within 6 hr of growth under hypoxic conditions. Previous studies showed that hypoxia activated proteasomedependent degradation of ERα (Stoner, Saville, Wormke, Dean, Burghardt, and Safe, 2002); however, the proteasome inhibitor MG132 did not reverse the hypoxia-dependent decrease in the induction of CYP1A1 protein by TCDD or the decrease in BRCA1 expression (Fig. 5B).…”

Section: Discussionmentioning

confidence: 72%

“…Hypoxia decreased estrogen-responsiveness in breast cancer cells (Stoner, Saville, Wormke, Dean, Burghardt, and Safe, 2002), and also decreases the magnitude of the antiestrogenic activity of AhR agonists in breast cancer cells (Fig. 1D).…”

Section: Discussionmentioning

confidence: 89%

“…TCDD inhibits E2-induced gene expression and reporter gene activity in breast cancer cells transfected with constructs containing E2-responsive promoter inserts (Duan, Porter, Samudio, Vyhlidal, Kladde, and Safe, 1999;Gillesby, Santostefano, Porter, Wu, Safe, and Zacharewski, 1997;Krishnan, Porter, Santostefano, Wang, and Safe, 1995;Porter, Wang, Duan, Qin, CastroRivera, and Safe, 2001;Safe and Wormke, 2003). Figure 1D shows that TCDD inhibited induction of luciferase activity by E2 in ZR-75 cells transfected with the E2-responsive pVEGF1 construct containing the -2018 to +50 insert from the VEGF promoter (Stoner, Saville, Wormke, Dean, Burghardt, and Safe, 2002). TCDD alone had minimal effects on activity.…”

Section: Discussionmentioning

confidence: 97%

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Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Khan

Liu

Stoner

et al. 2007

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-Erα crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1α or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFκB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 hr, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 hr, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 hr enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ahresponsiveness (under normoxia) that are also inhibited by cycloheximide.

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“…The evidence so far on an association of hypoxia, or factors such as CA9 that are induced by hypoxia, with resistance to endocrine therapy, however, is scarce. Hypoxia has been shown to lead to hormone insensitivity by ER degradation in breast cancer cell lines (Kurebayashi et al, 2001;Stoner et al, 2002). The level of VEGF, which is also induced under hypoxic conditions (Wykoff et al, 2000;Lal et al, 2001), predicts relapse in patients with breast cancer receiving adjuvant endocrine therapy more significantly than after polychemotherapy (Gasparini et al, 1999;Linderholm et al, 2000).…”

Section: Xmentioning

confidence: 99%

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

et al. 2003

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Here, we set out to assess CA9 expression levels by real-time quantitative RT -PCR in breast cancer tissue samples obtained from 253 patients, and correlated those with relapse-free (RFS) survival. The median follow-up time was 75 months (range 2 -168 months). CA9 expression was mainly found in high-grade, steroid receptor negative cancer tissues. CA9 levels were not significantly associated with RFS (P ¼ 0.926, hazard ratio (HR) ¼ 0.99, 95% CI ¼ 0.80 -1.22) in the total cohort of 253 patients. In multivariate analysis with other clinicopathological factors, CA9 (P ¼ 0.018, HR ¼ 0.77, 95% CI ¼ 0.62 -0.96), the interaction of adjuvant chemotherapy with CA9 (P ¼ 0.009, HR ¼ 1.31, 95% CI ¼ 1.07 -1.61) and the interaction of adjuvant endocrine therapy with CA9 (Po0.001, HR ¼ 1.41, 95% CI ¼ 1.20 -1.66) all contributed significantly to the final model. These results indicate that patients with low CA9 levels benefit more from adjuvant treatment than do patients with high levels. Thus, the determination of CA9 levels could aid in the selection of patients who will not benefit from adjuvant therapy, and whose prognosis will more likely improve with other treatment modalities.

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Hypoxia Induces Proteasome-Dependent Degradation of Estrogen Receptor α in ZR-75 Breast Cancer Cells

Cited by 101 publications

References 56 publications

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

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