TMEPAI, A Novel Therapeutic Target in Triple Negative Breast Cancer Prevention and Therapy


Year:

Session type:

Theme:

Prajjal Singha1,Srilakshmi Pandeswara2,Manjeri Venkatachalam3,Pothana Saikumar3
1University of Texas health Science center at San Antonio,2Department of Med/Hematology & Med Oncology. University of Texas Health Science Center at San Antonio, Texas, USA,3Department of Pathology, University of Texas Health Science Center at San Antonio, Texas, USA

Abstract

Background

Earlier we have shown that Transmembrane prostate androgen induced (TMEPAI), a novel transforming growth factor beta (TGF-β) inducible gene, converts tumor suppressive TGF-β into a tumor promoter in triple negative breast cancer (TNBC). We undertook the present study to screen drugs that can inhibit TMEPAI expression, growth, metastasis of TNBC cells.

Method

Cell culture, lentiviral vectors mediated endogenous TMEPAI knockdown, immunoblotting, migration, invasion, tumor xenografts, metastasis and cell proliferation assays were performed by the standard procedures.

Results

We identified a terpenoid derivative (TD) which inhibited the expression of TMEPAI, enhanced growth suppressive Smad dependent TGF-β signaling and blocked proliferation, migration and invasion of several triple negative breast cancer cells in vitro. Our results showed that TD increased phosphorylation of Smad2/3 and increased PTEN, p21 and p27 proteins that cause growth suppression in TNBC cells. Concurrently, TD decreased phosphorylation of Akt, MAPKs and reduced Snail and Slug that are required for cell growth and metastasis in TNBC cells. Interestingly, TD did not affect the growth of normal human mammary epithelial cells and failed to cause associated molecular changes that can result in growth suppression. Notably, using mice models (nude mice and syngeneic BALB/c mice), we found out that TD treated mice showed significant reduction in tumor burden derived from breast cancer cells compared to vehicle treated mice. Consistent with its ability to inhibit Akt phosphorylation and induction of Snail and Slug proteins, TD suppressed lung metastasis of TNBC cells in mice model. Importantly, reduced tumors derived from TD treated mice exhibited increased expression of pSmad2/3, PTEN, p21, p27 and reduced expression of pAkt compared to tumors obtained from vehicle treated mice.

Conclusion

Our findings suggest that drugs that target TMEPAI will not only inhibit growth and metastasis of TNBC cells but will also restore homeostatic functions of TGF-β to prevent new tumor development.