EXPERIMENTAL STUDY ON OVERCOMING RESISTANCE TO ENDOCRINE TEHRAPY IN BREAST CANCER

乳腺癌是一种与内分泌相关的癌症，内分泌治疗是治疗内分泌反应型乳腺癌的有效方法。然而，临床上经常出现对内分泌治疗的从头耐药和获得性耐药。虽然已经建立了大量对这些阻力负责的假设，但克服这些阻力的实用方法仍有待开发。为了探索这种方法，本课题进行了一项研究。为了建立内分泌耐药的乳腺癌细胞，我们建立了内分泌反应型人乳腺癌细胞系KPL-1和KPL-3C，在添加抗雌激素药物的培养液中培养了一年多。观察长期作用后细胞形态的变化及对细胞体外生长的促进作用。FUVESTRANT-RESIα的HER1表达水平升高，雌激素受体(ER)-…表达水平降低与亲本细胞相比，有更多的干细胞。耐药细胞对HER1/HER2双重抑制剂拉帕替尼的敏感性高于亲代细胞。我们还研究了拉帕替尼对人乳腺癌细胞株的加性或协同抗肿瘤作用。虽然拉帕替尼单独对KPL-1和KPL-3C细胞(ER阳性和HER1/HER2弱阳性)有较弱的抗肿瘤活性，但拉帕替尼和富维司琼联合治疗对这些细胞的生长有附加的抑制作用。这种附加的抗肿瘤活性与细胞周期蛋白依赖的激酶抑制物p21/p27的表达水平增加以及抗凋亡因子、bcl2和Survivin的表达水平降低有关。作为本项目研究的相关研究，我们对日本乳腺癌患者的免疫组织化学“固有亚型”进行了研究。已有研究表明，日本乳腺癌患者中腔A亚型(ER和/或孕激素受体[PR]阳性，HER2阴性，内分泌敏感，预后较好)和基底样亚型(ER阴性，PGR阴性，HER2阴性，HER1和/或细胞角蛋白5/6阳性，内分泌无反应，预后不良)的发生率高于不同种族的乳腺癌患者。较少

Breast cancer is one of endocrine-related cancers, and endocrine therapy is useful for the treatment of endocrine-responsive breast cancer. However, de novo resistance and acquired resistance to endocrine therapy are frequently seen in clinics. Although a large number of hypotheses responsible for these resistances have been created, practical methods for overcoming these resistances remain to be developed. To explore such methods, this project study was conducted.To establish endocrine-resistant breast cancer cells, endocrine-responsive human breast cancer cell lines, KPL-1 and KPL-3C, which were established at our laboratory, had been cultured in media supplemented with an antiestrogen fulvestrant for over a year. Morphologic changes in shape and promotion of cell growth in vitro were observed after the long exposure to fulvestrant. An increase in the expression level of HER1 and a decrease in the expression level of estrogen receptor (ER)-α were also observed in the fulvestrant-resi … More stant cells compared with the parental cells. The fulvestrant-resistant cells were more sensitive to a dual HER1/HER2 inhibitor, lapatinib, than the parental cells.We also investigated an additive or synergistic antitumor effect of lapatinib to fulvestrant in human breast cancer cell lines. Although lapatinib alone had a weak antitumor activity in KPL-1 and KPL-3C cells (ER-positive and HER1/HER2-weakly positive), a combined treatment of lapatinib with fulvestrant additively inhibited the growth of these cells. This additive antitumor activity was associated with an increase in expression levels of cyclin-dependent kinase inhibitors, p21/p27, and a decrease in expression levels of anti-apoptotic factors, Bcl-2 and survivin.Immunohistochemical “intrinsic subtype" was investigated in Japanese breast cancer patients as a related research to this project study. It has been indicated that the prevalence of luminal A subtype (ER and/or progesterone receptor [PR]-positive and HER2-negative, endocrine-responsive and better prognosis) is higher and that of basal-like subtype (ER-negative, PgR-negative, HER2-negative, HER1 and/or cytokeratin 5/6-positive, endocrine-non-responsive and bad prognosis) in Japanese breast cancer patients than that in breast cancer patients of different races. Less