High Expression of EIG121 Identifies Women with Triple Negative Breast Cancer with a Better Prognosis
L Deng, B Hennessy, R Broaddus. M.D. Anderson Cancer Center, Houston, TX
Background: Triple negative breast cancer is the most clinically aggressive form of breast cancer. Because they are defined by lack of ER, PR, and HER-2/neu, it is acknowledged that triple negative tumors are heterogeneous. 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 (good prognosis) from non-estrogen dependent non-endometrioid endometrial carcinoma (bad prognosis). We hypothesized that EIG121 may stratify patients with triple negative breast cancer into distinct prognosis groups.
Design: EIG121 expression was quantified using reverse phase protein lysate array (RPPA) in 460 breast cancers, 127 of these triple negative cases. RPPA is a high-throughput "dot blot" in which dilutions of protein lysate are spotted on nitrocellulose slides. Each slide is probed with a different monospecific antibody. A DAKO-catalyzed signal amplification system is used for signal detection. An advantage over immunohistochemistry is that RPPA is quantitative rather than qualitative. A tetracycline-inducible in vitro cell system was generated to analyze the effect of EIG121 in EGFR-mediated cell signaling, as EGFR is expressed in the majority of triple negative breast cancers.
Results: Overall, expression of EIG121 was low in triple negative tumors compared to ER+ cases. However, EIG121 expression was sufficiently heterogeneous to allow for stratification into EIG121 high and EIG121 low groups. The EIG121 high group had significantly increased recurrence free survival (hazard ratio 0.477; p=0.002) and overall survival (hazard ratio 0.565; p=0.032) compared to the EIG121 low group. EIG121 was significantly and negatively correlated with levels of EGFR, pEGFR, AKT, and pAKT. In the cell-based system system, EIG121 was shown to bind to and degrade EGFR.
Conclusions: High expression of EIG121 identifies triple negative breast cancer patients with improved survival. Breast cancers that over-express growth factor receptors are known to be biologically more aggressive. Therefore, the pro-survival effect of high EIG121 may be due, in part, to EIG121 directly inhibiting EGFR expression by lysosomal-mediated degradation.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 46, Tuesday Morning