EXPERIMENTAL STUDY ON ACTION MECHANISMS OF RESISTANCE TO HORMONAL THERAPY AND OVERCOMING THIS RESISTANCE IN BREAST CANCER

本研究项目的结果进行了总结。1）采用免疫组化方法检测原发性乳腺癌组织中HER 1、HER 2、p53的表达水平与复发性乳腺癌患者内分泌治疗反应的关系。HER 1过度表达的乳腺癌更早获得内分泌抵抗，并为患者提供更差的预后。2）在补充雌激素的条件下，HER 1-酪氨酸激酶抑制剂吉非替尼（G）增强了抗雌激素药氟维司群（F）在雌激素受体（ER）阳性人乳腺癌细胞中的抗肿瘤效果。这是因为G协同地增加了细胞周期蛋白依赖性激酶抑制剂p21的蛋白表达水平，并且该效果导致了附加的G1-S细胞周期延迟。此外，G诱导ER阴性和HER 1和/或HER 2过表达乳腺癌细胞中抗凋亡蛋白Bcl-2的表达水平降低和凋亡分数增加。3)Hypocytotoxins，tirapazamine和TX-402，抑制ER表达的人乳腺癌细胞移植到裸鼠的肿瘤中的减少。4）我们研究了在长期低氧暴露诱导的乳腺癌细胞中，与乳腺癌恶性进展相关的各种基因表达水平的变化。在几种乳腺癌细胞系中观察到HER 1表达水平的增加。此外，还观察到VEGF家族成员和HIF-1α的mRNA表达水平增加。这些实验结果表明，HER 1表达的增加可能在乳腺癌内分泌抵抗的发展中起重要作用。此外，它表明，缺氧细胞毒素或生长因子信号转导抑制剂的管理可能会延迟或克服乳腺癌的内分泌抵抗。

Results of this study project are summarized. 1)We investigated the relationship between the expression levels of HER1,HER2,p53 in primary breast cancer tissues by immunohistochemistry and responses to endocrine therapy in patients with recurrent diseases. HER1-overexpressing breast cancers acquired endocrine-resistance earlier and provided a worse prognosis to the patients. 2)A HER1-tyrosine kinase inhibitor, gefitinib (G), enhanced an antitumor effect of an antiestrogen, fulvestrant (F), in estrogen receptor(ER)-positive human breast cancer cells under estrogen-supplemented conditions. This is because G synergistically increased a protein expression level of a cyclin-dependent kinase inhibitor, p21, and this effect resulted in an additive G1-S cell cycle retardation. Additionally, G induced a decrease in an expression level of an anti-apoptotic protein, Bcl-2, and an increase in an apoptotic fraction in ER-negative and HER1 and/or HER2-overexpressing breast cancer cells. 3)Hypoxic cytotoxins, tirapazamine and TX-402, inhibited a decrease in ER expression in tumors transplanted with human breast cancer cells into nude mice. 4)We investigated changes in expression levels of various genes, which are associated with malignant progression of breast cancer, in breast cancer cells induced by a long-term exposure of hypoxia. An increase in an expression level of HER1 was observed in several breast cancer cell lines. Additionally, an increase in mRNA expression levels of VEGF family members and HIF-1α was observed. These experimental results suggest that an increase, in HER1 expression may play an important role in the development of endocrine-resistance in breast cancer. Furthermore, it is suggested that administration of hypoxic cytotoxins or inhibitors of growth factor signal transduction may delay or overcome endocrine-resistance in breast cancer.