Experimental Study on Overcoming Resistance to Hormonal Therapy in Breast Cancer

克服乳腺癌激素治疗耐药性的实验研究

基本信息

批准号：
12671187
负责人：
KUREBAYASHI Jyunichi
金额：
$ 1.66万
依托单位：
KAWASAKI MEDICAL SCHOOL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671187/
关键词：
Breast Cancer Hormone Resistance Hypoxia Estrogen Receptor Hypoxia-inducible Factor-Iα Vascular Endothelial Growth Factor Progesterone Recepter Cell Line VEGF 低酸素環境

项目摘要

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.

我们主张血管生成因子（例如VEGF和FGF）过表达在乳腺癌中抗激素治疗的抗性中的重要作用。最近的研究表明，低氧微环境在恶性细胞的进展中起重要作用。因此，我们假设增强了生殖因子的表达的低氧微环境可能会导致乳腺癌中的激素治疗的抗性。我们最近的研究揭示了一些证据支持我们的假设如下：1）在转录后和时间依赖性地依赖于下调雌激素受体（ER）（ER）的表达（A及其功能） - 雌激素通过雌二醇的生长刺激和孕激素受体诱导，2）低氧还降低了抗乳腺抗抗酸的生长抑制作用，MED抑制了ACET，MEDRECTRESS MEDROCTROTRODROXORTARTRONRO cORMESTRONTRONRO cORMESTROS，MEDROXOXOX蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白质蛋白质蛋白质蛋白质蛋白质蛋白质蛋白质蛋白质，组织，免疫组织化学分析表明，缺氧标记，低氧诱导因子（HIF）-L A的表达水平与乳腺癌细胞中ER- A的表达水平成反比。此外，我们进行了一项研究，研究了新型HSP90抑制剂的作用，由Kyowa Hakko Kogyo Co.，Ltd.提供的KF58333。我们首次发现该药物下调了HIF-1 a的蛋白质表达水平。和在我们研究所建立的耐激素的人类乳腺癌细胞系KPL-1中的VEGF。我们最近的研究的发现表明，低氧微型视神经诱导乳腺癌中激素耐药性的发展，而某种抑制HIF-1 A表达的药物可能会克服这种抵抗力。在我们的实验室中，正在研究使用低氧毒素的进一步研究，以阐明我们的假设并找到有希望的药物，这些药物可以克服乳腺癌中对荷尔蒙治疗的耐药性。