Abstract 2526: PMEPA1 gene isoforms indicated aggressive disease progression in non-prostate solid tumors

Abstract Introduction: Abnormal activation of androgen and TGF-β signaling play important roles in tumorigenesis of various solid tumors including prostate, lung and colon cancers. As an androgen and TGF-β responsive gene, PMEPA1 has been defined to regulate androgen and TGF-β signaling via negative feed-back loops. Our lab recently established that PMEPA1 distinct isoforms (isoforms a, b, c, d and e) with disparities within N-terminus protein sequences navigated different regulations of androgen/TGF-β signaling. In this study, the expressions and the correlations to disease progression of PMEPA1 isoforms were investigated in prostate, breast, lung and colon cancers. Methods: RNA seq data from total 2479 solid tumor samples in the TCGA dataset were used to study the correlation between expressions of PMEPA1 isoforms and disease progression including Gleason score, pathology stages, progression free survival rate (PFS) and overall survival rate (OS). The cohort is composed of 482 prostate, 1049 breast, 499 lung and 449 colon cancer patients. Results: In prostate cancer, TCGA data analysis showed that lower transcript level of PMEPA1-b isoform associated with higher Gleason scores and lower progression free survival rate (PFS) (P=0.014) and worse overall survival rate (OS) (P<0.01). The ratio of mRNA levels of PMEPA1-a versus PMEPA-b indicated higher Gleason score, lower PFS rate (P=0.0063) and worse OS rate (P=0.0042). In contrast, higher expression of both PMEPA1-a and PMEPA1-b associated with lower PFS (P=0.023 and 0.028, respectively) in breast cancer. And the enhanced ratio of PMEPA1-a/b was also found to indicate lower PFS (P=0.016) and worse OS (P=0.016) in breast cancer. Similarly, the increased transcript levels of PMEPA1-a and PMEPA1-b isoforms significantly associated with lower PFS and worse OS rates in lung and colon cancer. The expressions of PMEPA1 isoforms were not found to associate with pathology stages of non-prostate tumors. Interestingly, our data further showed that the expressions of both PMEPA1-a and PMEPA1-b isoforms were positively correlated to TGF-β responsive genes including COL1A and THBS1 in breast cancer, lung adenocarcinoma, lung square cancer and colon cancers, which may indicate non-androgen regulation mechanism of PMEPA1-b isoform in non-prostate context. Conclusions: Our data establish the biomarker potential of PMEPA1 isoforms (a and b) indicating more aggressive disease progressions in 4 solid tumors, further underscoring the PMEPA1 isoform specific biological functions to differentiate regulation of androgen and TGF-β signaling in various organ specific contexts. Citation Format: Shashwat Sharad, Zsófia M. Sztupinszki, Zoltan Szallasi, Shiv Srivastava, Alagarsamy Srinivasan, Albert Dobi, Hua Li. PMEPA1 gene isoforms indicated aggressive disease progression in non-prostate solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2526.