EXPERIMENTAL STUDY ON OVERCOMING RESISTANCE TO ENDOCRINE TEHRAPY IN BREAST CANCER

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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