Impact Of Hypoxia On Estrogen Receptor Alpha In Human Breast Carcinoma

Impact of Hypoxia on Estrogen Receptor Alpha in Human Breast CarcinomaDepartment of Surgery, Cancer Hospital/Cancer Institute, Fudan UniversityPh.D. Candidate: Liu Guang-YuSupervisor: Shen Zhen-Zhou Purpose: Hypoxia is common in breast cancer and may influence gene expression to promote malignancy. Estrogen receptor (ER)-( status is an important predictor for both prognosis and clinical response to endocrine therapy. The aim of our current study is to demonstrate the impact of hypoxia on ER-α in both breast cancer tissue and cell lines. Experimental Design: We have examined ER-α expression in breast cell lines and by immunohistochemistry in parallel with indicators of hypoxia in 51 ER-α ligand binding assay positive breast tumors for in-vivo evidence of this phenomenon. Results: Overall, 49 tumors were ER-α positive by immunohistochemistry. Regional loss of ER-α expression was consistently present in peri-necrotic as compared to distant regions in both in-situ (n=29, p<0.0001) and invasive (n=20, p=0.0001) carcinomas and was closely associated with regions of hypoxia defined by the proximity of necrosis and induction of hypoxia induced genes CA-IX and Glut-1 (p<0.0001). Examination of ER-α expression in breast cancer cell lines in both protein and mRNA level confirmed that this phenomenon can be directly attributed to hypoxia and not to other stress factors likely to be present in regions adjacent to necrosis, such as reduced glucose and low pH, and products released from necrotic or hypoxic cells. In addition we have found that chronic intermittent hypoxia can cause persistent downregulation of ER-α in the MCF-7 breast cell line. Conclusions: Regional hypoxia in breast tumors is associated with reduced ER-α expression and intermittent hypoxia can cause persistent downregulation. Hypoxia may therefore contribute to progression to ER-α negative status and potentially to reduced response and development of resistance to endocrine therapy.