Abstract P2-01-14: Adipocytes and cancer cell interactions promote leptin receptor expression and drive β-catenin-mediated progression in triple negative breast cancer

Abstract

Abstract Background Triple negative breast cancer (TNBC) patients suffer from poor prognosis due to short-term recurrence and/or metastasis. Obesity is reported to predict poor prognosis of TNBC. However, the mechanisms connecting obesity to progression of TNBC remain unclarified. Methods We co-cultured TNBC model cells with adipocytes differentiated from human adipose-derived mesenchymal stem cells (hMSC-ad) and TNBC patients derived primary adipocytes to examine migration, invasion and metastasis abilities using Transwell assays and tail vein injection xenograft mouse model, respectively. Expression levels of leptin receptor (LEPR) , epithelial-mesenchymal transition (EMT) markers and β-catenin signaling pathway related molecules in the control and co-cultured TNBC model were analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and western blot assays. Downregulation of LEPR by LEPR specific short hairpin RNA (shRNA) and upregulation of the downstream pathway with continuous activated β-catenin were applied to access their roles in adipocytes and cancer cell interactions. Degree of adipocytes infiltration in tumor tissue was evaluated by histopathology. LEPR mRNA expression level in breast cancer and corresponding patients' information was retrieved from The Cancer Genome Atlas (TCGA) database. Results Here we first reported that both hMSC-ad- and patients-derived adipocytes promoted migration and invasion of TNBC model cells in vitro and lung metastasis in vivo. Adipocytes were then confirmed to induce upregulation of LEPR in each TNBC model cell compared to the control groups (p<0.0001), resulting in higher expression of EMT markers and molecules related to β-catenin signaling pathway.Afterwards, LEPR knockdown led to decreased migration, invasion and metastasis capacities, as well as reduced expression of EMT markers and molecules related to ?-catenin signaling pathway, while activation of ?-catenin could restore robust EMT and metastatic abilities of TNBC model cells. Last, clinical specimen analyses showed that infiltration of adipocytes to tumor tissue was significantly associated with shorter DFS of TNBC patients (p<0.05) and upregulated LEPR in breast cancer tissue indicated poor prognosis (median OS of 7.43 vs 10.81 years of the LEPR-low group, p < 0.05). Conclusions To our knowledge, adipocytes are first shown to promote progression of TNBC via previously uncharacterized LEPR-β-catenin signaling pathway. Citation Format: Feng Z, Tao Z, Hu X. Adipocytes and cancer cell interactions promote leptin receptor expression and drive β-catenin-mediated progression in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-14.