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Intermittent Hypoxia Induces Proteasome-Dependent Down-Regulation of Estrogen Receptor in Human Breast Carcinoma

Manitoba Institute of Cell Biology and Departments of ¹ Pathology and ² Biochemistry and Medical Genetics, University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada; and ³ Department of Surgery, Cancer Hospital/Cancer Institute, Fudan University, Shanghai, China

Purpose: Hypoxia may influence gene expression to promote malignancy, and acute hypoxia has been shown to transiently repress estrogen receptor (ER)- expression in breast cell lines. However, the effect of intermittent hypoxia, which is likely more prevalent in breast cancers, remains to be determined.

Experimental Design: ER- expression was assessed by Western blot and immunohistochemistry in a selected cohort of 51 ER-–positive breast carcinomas, in relation to markers of hypoxia. The effect of acute and intermittent hypoxia on ER- expression was also determined in MCF7 and ZR-75 breast cell lines, together with the role of proteasome function with the proteasome inhibitor bortezomib.

Results: Regional loss of ER- expression occurs in breast tumors and is consistently present in hypoxic regions defined by the proximity of necrosis and induction of hypoxia-induced genes carbonic anhydrase IX (CA-IX) and glucose transporter 1 (Glut-1), in both in situ (n = 29; P < 0.0001) and invasive (n = 20; P = 0.0001) carcinomas. In MCF7 and ZR-75 cells, ER- is transiently down-regulated by acute hypoxia and rapidly restored by reoxygenation. However, intermittent, acute hypoxia can cause a similar down-regulation of ER- that is not attributable to decreased mRNA and persists in MCF7 cells despite reoxygenation for up to 14 days. This effect occurs with no change in cell viability but a corresponding reduction in growth response to estradiol. However, ER- expression can be restored by bortezomib.

Conclusions: Intermittent hypoxia can cause persistent changes in proteasome function that may contribute to reduced ER- expression in breast tumors and consequently to diminished response and development of resistance to endocrine therapy.

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