Abstract P2-10-06: Ethnicity-dependent alternative RNA splicing variations of estrogen receptor in breast cancer

Background: African-American (AA) women are more likely to have poorer outcomes and die of breast cancer than European Ancestry (EA) women, even among patients with similar stage and tumor subtype. Despite the higher incidence of aggressive triple-negative breast cancer (TNBC) in AA women, the greatest survival disparities are observed within the “good-prognosis” estrogen receptor receptor-positive (ERpos) subtypes. This exists even after correcting for the socioeconomic factors suggesting the distinct biological basis for disparities. Understanding the factors underpinning breast cancer disparities is critical to reduce the disparity-related poor outcomes. We hypothesized that Alternative RNA splicing (ARS) of estrogen receptor could influence the tumor aggressiveness and particularly, response to therapy. To this end, we examined the expression of estrogen receptor (ER) transcripts in AA and EA ethnicity groups in breast cancer. Design: The effect of ethnicity on alternative RNA splicing of ER was explored using BRCA-TCGA data and a web-based tool for splicing variants analysis. The significance of ESR1 transcripts with respect to race, ER, Progesterone receptor (PR) and tumor stage was analyzed using JMP statistical package. Results: Expression of the 27 ESR1 transcripts were analyzed in 838 cases (705 EA and 133 AA). Of these 27 transcripts, 16 were expressed in TCGA-BRCA cohort. The majority of these cases belonged to ERpos/PRpos/HER2neg group (n=339; 308 EA and 31 AA). Differential expression of four transcripts (isoform_uc003qom, P = 0.0047; isoform_uc010kio, P = 0.0345; isoform_uc010kir, P = 0.0492 and isoform_uc011eev, P = 0.0066) were significant in AA compared to EA women; all of these were lower in AA. Similar analyses by Stage in this group demonstrated that overall ESR1 levels were associated with tumor stage but none of the individual transcripts exhibited similar association. In ERpos/PRneg/HER2neg subgroup (n=61; 48 EA and 13 AA), two transcripts (isoform_uc010kir, P = 0.028 and isoform_uc011eey, P = 0.0435) retained significance suggesting the important interaction of PR with race. As expected, most of the ER transcripts were not significant in 112 TNBC (78 EA and 34 AA) patients except for the isoform_uc010eev, P = 0.0354. In ERpos/PRpos/HER2pos cases (n=89; 81 EA and 8 AA), isoform_uc010kir, P = 0.0056 and isoform_uc010kis, P = 0.0365 were significantly differentially expressed by race. There was no difference in transcript expression in HER2pos group (n=29; 22 EA and 7AA). Conclusions: Dramatic variation in ESR1 transcript expression was observed in AA versus EA populations. These variations were further affected by ER and PR status. As variations in transcript expression can have a striking impact on mRNA stability and translation efficacy, better understanding of transcript differences is necessary. The observed results have several important implications for clinical management and could explain some of the differences in responses to endocrine therapy observed in association with ethnicity dependent health disparities. Citation Format: Yesim Gokmen-Polar, Sunil S Badve. Ethnicity-dependent alternative RNA splicing variations of estrogen receptor in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-06.