The Novel Estrogen-Induced Gene EIG121 Is Up-Regulated in Estrogen Receptor Positive Breast Cancer, Significantly Associated with Recurrence Free and Overall Survival, and Is Associated with Sensitivity to Tamoxifen
L Deng, B Hennessy, R Broaddus. M.D. Anderson Cancer Center, Houston, TX
Background: The development of endocrine resistance in estrogen receptor (ER) positive breast cancers represents a significant obstacle in the clinical managment of breast cancer patients. The mechanisms underlying such resistance, however, are unknown. We discovered the novel gene EIG121 from a microarray of baseline and post-treatment endometrial biopsies from women taking estrogen-based hormone replacement therapy. EIG121 is a lysosomal protein up-regulated in endometrioid-type endometrial carcinoma, the histotype most closely associated with unoppposed estrogen exposure. In fact, EIG121 is the single best gene to discriminate endometrioid carcinoma from non-estrogen dependent non-endometrioid endometrial carcinoma. Because of these interesting expression characteristics in endometrial cancer, we hypothesized that EIG121 would be tightly linked to ER positive breast cancer and may play a role in determining hormone responsiveness.
Design: EIG121 expression was quantified using qRT-PCR in 30 normal and breast cancer tissues and by applying reverse phase protein lysate array (RPPA) in 460 breast cancers. EIG121 expression was also analyzed in tamoxifen-sensitive and -resistant MCF7 breast cancer cells. A tetracycline-inducible cell system was generated to analyze the effect of EIG121 in EGFR-mediated cell signaling, as this pathway has been hypothesized to mediate endocrine resistance.
Results: EIG121 was strongly over-expressed in ER positive breast cancers compared to normal breast tissue and ER negative cancers. In multivariate analysis of the RPPA data, high EIG121expression was a significant predictor of both recurrence free survival and overall survival. In 258 of the patients with ER positive cancers treated with adjuvant tamoxifen, high levels of EIG121 were significantly associated with recurrence free survival (p=0.0364). EIG121 was over-expressed in tamoxifen-sensitive breast cancer cells, but not detected in tamoxifen-resistant cells. EIG121 binds to EGFR, promoting its degradation and inhibiting downstream signaling via Akt.
Conclusions: The expression characteristics of EIG121 in breast cancer suggest that it is strongly associated with factors important in survival. Furthermore, our experiments in cell-based systems suggest that EIG121 plays a direct role in determining a breast cancer cell's sensitivity to endocrine-based therapy.
Monday, March 9, 2009 1:00 PM
Poster Session II # 46, Monday Afternoon