Abstract 1392: Role of mutant p53 for anti-TGF-β therapy in isogenic basal-like breast cancer models.

Abstract

Abstract Breast cancer remains as one of the most common cancers worldwide accounting for 450,000 deaths. During cancer progression, transforming growth factor-β (TGF-β) signaling in tumor cells is often converted from tumor suppression to tumor promotion. However, how this oncogenic switch occurs is not well understood. Tripe-negative breast cancer (TNBC) is a breast cancer subtype, which is frequently associated with p53 mutation and lacks specific molecular targets for therapeutic intervention. TGF-β signaling has been shown to be oncogenic in TNBC models. Therefore, we tested the hypothesis that mutation of p53 may cause the oncogenic switch of TGF-β and thus serve as a biomarker for anti-TGF-β therapy. In an effort to create isogenic models resembling the transformation of normal breast epithelial cells into TNBC, oncogenic H-Ras V12, human telomerase reverse transcriptase (hTERT), and mutant p53 R175H (mP53) or vector control were sequentially introduced into untransformed human breast epithelial MCF-10A cells. These generated cell lines were orthotopically introduced into the mammary fat pads of female nude mice and tumor burden was monitored. Mice were divided into two groups receiving a TGF-β type I receptor (RI) kinase inhibitor or PBS as control. Harvested lungs were analyzed for metastasis with GFP fluorescent imaging and quantitative PCR for tumor cell specific genes. Mice inoculated with the transformed MCF-10A cells containing mp53 (10A/mp53) displayed greater tumor burden and lung metastasis incidence than the vector control counterparts. Systemic treatment with the TGF-β inhibitor resulted in a decrease in metastasis in the mice inoculated with 10A/mp53 representing disruption of TGF-β’s oncogenic role. In contrast, inhibition of TGF-β signaling in mice inoculated with 10A/pp290 vector control displayed greater lung metastasis incidence, likely due to the disruption of TGF-β tumor suppressive effects. Our results indicate that the mp53 may serve as a biomarker for the oncogenic switch of TGF-β pathway and anti-TGF-β therapy for the inhibition of TNBC-induced metastasis. Citation Format: Fernando P. Lugo, Shu Lin, Abhik Bandyopadhyay, Junhua Yang, Lu-Zhe Sun. Role of mutant p53 for anti-TGF-β therapy in isogenic basal-like breast cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1392. doi:10.1158/1538-7445.AM2013-1392