title: Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.
abstract: A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha 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 ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ 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 ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis.
authors.affiliation: Lombardi Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Michele K
authors.initials: MK
authors.lastname: Dougherty
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schumaker
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.forename: Wade V
authors.initials: WV
authors.lastname: Welshons
authors.forename: Edward M
authors.initials: EM
authors.lastname: Curran
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Dorraya
authors.initials: D
authors.lastname: El-Ashry
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D016895:Culture Media, Serum-Free; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D011987:Receptors, Steroid / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016895:Culture Media, Serum-Free; D047628:Estrogen Receptor alpha; D011987:Receptors, Steroid; D004958:Estradiol; D017239:Paclitaxel