Estrogen-regulated gene expression predicts response to endocrine therapy in patients with ovarian cancer

Abstract

Objective To explore the predictive value of estrogen-regulated gene changes as indicators of sensitivity in ovarian cancer patients treated with the aromatase inhibitor Letrozole. Methods Expression of a range of proteins was assessed by semi-quantitative immunohistochemistry in tissue sections from the tumors of patients treated with Letrozole. Expression was correlated with clinical response to Letrozole. Corresponding mRNA in ovarian cancer cell lines treated with 17β-estradiol (E 2) was measured by quantitative RT-PCR. Results In an estrogen receptor (ER)-positive ovarian cancer cell line, quantitative RT-PCR analysis demonstrated that PLAU, VIM, BIGH3, CDH6, FN1, CASP4, KRT4, KRT7, KRT13, TRAM and NGAL were down-regulated and TFF1, TFF3, TRAP1, TFAP4, MYC, CTSD, IL17BR, TOP2A, CCNB1, CCNB2, PDZK1 and UBE2C were up-regulated by E 2. The E 2 modulation of these genes was reversed by the anti-estrogen tamoxifen and was ERα-dependent. For ovarian cancer patients treated with Letrozole, we tested the predictive value of the majority of these genes in paraffin sections from their primary tumors by semi-quantitative immunohistochemistry. Significant differences in expression levels of TFF1, TFF3, BIGH3, TRAP1, VIM, TOP2A, PLAU and UBE2C were observed between tumors from CA125 responsive/stable patients as opposed to tumors from patients whose disease progressed, using serum levels of CA125 as an indicator of response. Aromatase expression in the ovarian cancers also differed between these 2 groups of patients. Conclusion These results suggest that expression levels of certain proteins in ovarian cancers are estrogen-regulated and could help identify patients who would benefit from endocrine therapy.