Fulvestrant (ICI 182,780) sensitizes breast cancer cells expressing estrogen receptor α to vinblastine and vinorelbine

Abstract

Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor alpha positive (ER+) breast tumors than ER negative (ER-) tumors, which has raised a clinically relevant question as to how to reverse this ER-mediated chemoresistance in ER+ breast tumors. This study is to investigate the possible influence of estrogen receptor alpha (ERalpha) on the therapeutic effects of vinblastine and vinorelbine on breast cancer cells and explore whether combination of anti-estrogen agent fulvestrant (ICI 182, 780) may enhance the sensitivity of ERalpha+ cells to these chemotherapeutic agents. Through comparing ER+ with ER- human breast tumor cells or through stable transfection of an ERalpha expression vector into ER negative human breast cancer BCap37 cells, a series of assays were applied to determine the sensitivity of ER+ and ER- breast tumor cells to vinblastine and vinorelbine in the presence or absence of 17-beta-estradiol and/or fulvestrant. 17-beta-Estradiol showed no effect on the sensitivity of ER- MDA-MB-468 and BCap37 cells to the treatment of vincristine or vinblastine, but it significantly reduced the sensitivity of ER+ T47D cells and BCap37 cells expressing ERalpha to the two drugs mentioned. Further analyses show that ERalpha has little effect on vinca alkaloids-induced mitotic arrest, but dramatically affects their ability to induce tumor cell apoptosis. Moreover, through a series of assays, we also demonstrated that the combination of fulvestrant, a selective ER down-regulator, could reverse the resistance of ER+ breast tumor cells to vinca alkaloids and even produce synergistic effects. The findings obtained from this study have provided important evidence that expression and subsequent activation of ERalpha are associated with resistance of breast cancer cells to vinca alkaloids. This study also suggested that the combination of anti-estrogen agents, such as fulvestrant, might be a novel strategy to reverse ER-mediated chemoresistance or sensitize ER+ breast tumors to vinca alkaloids and possibly other chemotherapeutic agents.

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

“…Our results provide the first evidence that dovitinib treatment sensitizes FGFR2 mutant cells to pure steroidal selective ER modulators such as ICI182.780. In breast cancer, some authors have reported in vitro and in vivo assays using combinational therapy using ICI182.780 with chemotherapeutic agents such as Doxorubicin (46); Paclitaxel (47), Vinorelbine (48), and Doxotaxel (49), although the results are quite promising, the number of studies is limited and combinational treatment using modern hormone therapy with chemotherapeutic agents has not been examined toughly; specially in endometrial carcinoma treatment. However, several experimental approaches using anticancer kinase inhibitors in tumor cells have revealed numerous feedback loops and have shown that blocking one signaling pathway can block tumor growth partially, but they are not sufficient to cause a complete tumor regression, thereby allowing resistant cells to emerge (50).…”

Roles and Mechanisms of Estrogen and Estrogen Receptors in Breast Cancer Resistant to Chemotherapy

“…E2 also independently activated extracellular signal-regulated protein kinase activity, which contributed to the antiapoptotic effects. In addition, our recent studies also demonstrated that E2 significantly inhibited paclitaxel or vinca alkaloids-induced phosphorylations of bcl-2 and c-raf-1, as well as the degradation of IB in BCap37 cells transfected with ER, which was accompanied with decreased sensitivity of BC-ER cells to the above anticancer drugs (7,8). In response to various extracellular and intracellular signals, p53 mediates cellular processes, such as apoptosis, cell cycle arrest, and senescence, depending on the signal and the cellular context (49)(50)(51).…”

“…Neoadjuvant chemotherapy has a well-established role in the management of early-stage, operable breast cancer, and remains the gold standard downstaging systemic therapy in many centers, regardless of ER status. However, the data from other clinical trials or retrospective analyses suggest that ER status might also affect the efficacy of chemotherapy (5)(6)(7)(8). Specifically, it has been observed that some chemotherapeutic agents may be less effective in patients with ER+ tumors than those with ER-tumors.…”

“…More recently, in a retrospective clinical study conducted by us and our collaborators, we found that primary breast cancer patienhts with ER+ tumors achieved significant lower pathologic response than those with ER-breast tumors when treated with preoperative chemotherapeutic regimens including DEC (docetaxel+epirubicin+cyclophosphamide), VFC (vinorelbine/vincristine+5-fluorouracil+ cyclophosphamide) and EFC (epirubicin+5-fluorouracil+cyclophosphamide) (34). The involvement of ER in chemoresistance has also been confirmed in a number of in vitro studies (5,7,8,(35)(36)(37)(38)(39)(40). For example, ER-breast cancer tissue was found chemosensitive in vitro compared with ER+ tissue against six antitumor drugs including carboquone, adriamycin, mitomycin C, aclacinomycin A, cisplatin and 5-fluorouracil (5).…”

“…However, these responses were significantly reversed by incubation with E2, which was probably mediated through the plasma membrane estrogen receptor (40). Recently, we established several isogenic ER+ cell lines by stable transfection of ERexpression vectors into ER-breast cancer BCap37 cells to investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and vinca alkaloids (7,8). We found that 17- estradiol significantly reduced the overall cytotoxicity of these antimicrotubule drugs in ER-expressing BCap37 but had no influence on the ERparental cells or ER-MDA-MB-468 cells.…”