Estrogen Receptor Expression and Sensitivity to Paclitaxel in Breast Cancer

Abstract

ACKNOWLEDGEMENTS Research Paper Estrogen Receptor Expression and Sensitivity to Paclitaxel in Breast Cancer ABSTRACTA retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERα negative (ERα-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERα and the effectiveness of adjuvant paclitaxel reflects the observation that ERα positive (ERα+) breast cancers proliferate more slowly than ERα-breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxelinduced apoptosis in ERα+ and ERα-clones of the same, originally ERα+ cell line. For the T47D and ZR-75 cell lines, loss of ERα was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERα-clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERα+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERα expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERα analysis.

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

“…Cumulative data from clinical observations and retrospective analyses suggested that ER status might affect the therapeutic efficacy of paclitaxel because it has been observed that paclitaxel exhibited less effect in patients with ER+ breast tumors than those with ER tumors (7,9,16). Moreover, the phenomenon of ER-mediated resistance to paclitaxel has also been observed in in vitro experiments (17,41). However, most of these results were obtained based on comparative studies between the tumor cell lines derived from different individuals (17).…”

“…However, most of these results were obtained based on comparative studies between the tumor cell lines derived from different individuals (17). Although some paired cell lines were derived under the selective pressure of a low/no estrogen environments, these tumor cells are still not likely to be isogenic because many features, including their proliferative capacity, might have changed due to genetic alterations (41). Thus, it is difficult to elucidate the cellular and molecular mechanisms.…”

Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment

“…Vikhanskaya et al (1998) reported that the inactivation of p53 is susceptible to Paclitaxel in ovarian cancer (Rouzier et al, 2005), and Reinecke et al (2000a, b) described the expression and function of P-glycoprotein in renal cell carcinoma. Moreover, the overexpression of antiapoptotic genes (Wang et al, 2005), the upregulation of cyclin A (Takahashi et al, 2005), the overexpression of oestrogen receptor (Dougherty et al, 2004), and the reduced expression of tau (Rouzier et al, 2005) have all been reported as Paclitaxel susceptibility markers in breast cancer. As for colorectal cancers, the expression of MDR-1, bcl-2, and bax each contribute to Paclitaxel sensitivity (Sharma et al, 2000).…”

Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer

“…ZR75.1 and MCF-7 cells were used for further in vitro studies. These cells are known to be relatively resistant to paclitaxel (14). T47D and MDA-MB 435 cells could not be successfully transfected with anti-tau siRNA.…”