| Research Abstract |
We have advocated the significant role of overexpression of angiogenic factors, such as VEGF and FGF, in the development of resistance to hormonal therapy in breast cancer. Recent studies have suggested that a hypoxic microenvironment plays an important role in the progression of malignant cells. Therefore, we hypothesized that the hypoxic microenvironment, which enhances the expression ofangiogenic factors, may cause the resistance to hormonal therapy in breast cancer. Our recent studies revealed some evidence supporting our hypothesis as follows : 1) hypoxia post-transcriptionally and time-dependently down-regulated the expression of estrogen receptor (ER)- a and its functions, such as growth-stimulation and progesterone receptor-induction by estradiol, 2) hypoxia also decreased the growth-inhibitory effect of antiestrogen and a progestin, medroxyprogesterone acetate, 3) in breast cancer tissues, immunohistochemical analysis revealed that the expression level of a hypoxia marker, hypoxia-inducible factor (HIF)-l a, inversely correlated with the expression level of ER- a in breast cancer cells. In addition, we conducted a study investigating the effects of a novel Hsp90 inhibitor, KF58333 provided from Kyowa Hakko Kogyo Co., Ltd. We have found for the first time that this agent down-regulated a protein expression level of HIF-1 a. and VEGF in a hormone-resistant human breast cancer cell line, KPL-1, which was established in our institute. Findings from our recent studies suggest that hypoxic microenviromnment induces the development of hormone resistance in breast cancer and a certain agent, which inhibits HIF-1 a expression, may overcome such resistance. Further studies using hypoxic toxins are under investigation in our laboratory to clarify our hypothesis and to find promising agents, which can overcome the resistance to hormonal therapy in breast cancer.
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