Estrogen Receptor α Mediates Breast Cancer Cell Resistance to Paclitaxel through Inhibition of Apoptotic Cell Death

Abstract

Estrogen receptors (ER) are expressed in f65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ERÀ) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ERA expression vectors into ERÀ breast cancer BCap37 cells. We showed that 17-B estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ERA but has no influence on the ERÀ parental cells. Further analyses indicate that expression of ERA in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ERA-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ERA and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ERmediated resistance to paclitaxel and possibly other antineoplastic agents. [Cancer Res 2007;67(11):5337-44]

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

“…(Anand et al 2003, Yang et al 2006. Also known is that estrogen protects breast and ovarian cancer cells from taxol-induced apoptosis (Mabuchi et al 2004, Sui et al 2007. Based on our data that Aurora-A downregulation can override E 2 -induced growth and transformation, we speculated that downregulation of Aurora-A might counteract the estrogen-mediated decrease in Doc sensitivity as well.…”

“…Alternatively, in addition to being pro-proliferative, estrogen has been shown to be a survival factor also. Estrogen has been shown to abrogate the apoptotic response of ovarian cancer cells to paclitaxel (Mabuchi et al 2004) and ER-positive breast cancer cells tend to be more resistant to anti-neoplastic drugs such as paclitaxel and Doc (Sui et al 2007). On the other hand, Aurora-A has been emerging as on anti-cancer target for reasons related to its role in cell cycle regulation, checkpoint evasion, centrosome amplification, and aneuploidy.…”

Epigenetics and Breast Cancer

“…In addition to these highly characterized mutations, epigenetic alterations resulting in aberrant gene expression are key contributor to breast tumorigenesis (Campan et al, 2006;Giacinti et al, 2006;Mirza et al, 2007;Sharma et al, 2005;Sui et al, 2007;VincentSalomon et al, 2007;Visvanathan et al, 2006;Zhou et al, 2006. Decreased methylation of repetitive sequences in the satellite DNA of the pericentric region of chromosomes is associated with increased chromosomal rearrangements, mitotic recombination, and aneuploidy (Eden et al, 2003,Karpf andMatsui, 2005).…”

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

“…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).…”