OBJECTIVETo demonstrate the impact of hypoxia on ER-alpha in both breast cancer tissue and cell line, and its relationship with hypoxia-related parameters.

METHODSExpression of ER-alpha in 51 breast cancer patients with ER positive determined by ligand-binding assay was examined by immunohistochemistry and compared with CA-IX and Glut-1. Impact of hypoxia on breast cancer cell line MCF-7 (ER-alpha positive) was observed by Western Blot and RT-PCR.

RESULTSOf 51 breast cancer patients, 49 were ER-alpha positive. Regional decrease of ER-alpha expression was consistently observed in peri-necrotic regions as compared to distant regions in both in-situ carcinomas (n=29, P <0.0001) and invasive carcinomas (n=20, P=0.0001), which was closely associated with the induction of CA-IX and Glut-1 in hypoxia (P <0.0001). The decreased expression of ER-alpha protein and mRNA in breast cancer cell lines were attributed to hypoxia and not to other stress factors, such as reduced glucose, low pH, and products released from necrotic or hypoxic cells. Chronic intermittent hypoxia could cause persistent down-regulation of ER-alpha in the MCF-7 breast cancer cell line.

CONCLUSIONRegional hypoxia in breast cancer is associated with the reduced ER-alpha expression, and intermittent hypoxia can cause persistent down-regulation. Hypoxia may therefore contribute to the progression of ER-alpha negative status and potentially to the development of resistance to endocrine therapy.