Abstract 1995: PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression

Abstract

Abstract Parathyroid hormone-related peptide (PTHrP) was first discovered in cancer patients as the primary cause of malignancy associated hypercalcemia (MAH) & is overexpressed in most human breast tumors. We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer progression can dramatically prolong tumor latency, slows tumor growth & metastases. Here we examined the signaling pathways under the control of PTHrP in the pre-neoplastic stage of tumor development (hyperplasia) by generating MMTV-PyMT model in which the mammary epithelium, expressing membrane-targeted GFP, is distinguished from the membrane-targeted red fluorescent backlight of stromal & nonepithelial-derived mammary tissues. We constructed Pthrpflox/flox; Cre+ mT/mG tumor mice (PTHrP conditional KO) & Pthrpwt/wt; Cre+ mT/mG tumor mice (WT control). Next, we applied FACS to enrich the GFP+ mammary epithelial cells isolated from PTHrP KO & control tissues for subsequent RNAseq analyses. We then examined differentially expressed genes (DEGs) by comparing purified cell populations from PTHrP KO & control tissues. We identified 939 DEGs (p value <0.01) & used DAVID bioinformatics resources to systematically analyze the KEGG pathways. Among the most significant pathways, extracellular matrix (ECM), focal adhesion,PI3K-Akt, RAS and WNT pathways were up-regulated in WT control cells compared to KO cells. In summary, PTHrP controls critical signaling pathways involved in breast cancer initiation at the pre-neoplastic stage & suggests that PTHrP ablation is a promising therapeutic strategy in breast cancer. Citation Format: Rui Zhang, Jiarong Li, Dunarel Badescu, Andrew Karaplis, Jiannis Ragoussis, Richard Kremer. PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1995.