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

点击翻译按钮获取中文摘要

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.