Abstract LB-055: Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancer

Abstract

Abstract Breast cancer studies implicate the discoidin domain receptor 1 (DDR1) in both pro- and anti-tumor roles. DDR1 is often overexpressed in breast tumors and its activation by collagen promotes tumor cell invasion and potentiates metastatic colonization by cell lines. However, DDR1 transfection into low DDR1 expressing tumor cells hinders cell migration. Moreover, low expression of DDR1 correlates with higher grade human tumors and associates with worse prognosis. To better understand the role of DDR1 in breast tumor progression and metastasis, we established a DDR1 knockout and crossed it into the MMTV-PyMT mouse. DDR1 loss compromised luminal cell adhesion and expanded the basal/myoepithelial population in adult mice. PyMT DDR1-/- tumors grew faster and had increased lung metastasis both in size and number of metastatic colonies. The DDR1-/- tumors broadly exhibited a more basal-like phenotype with enhanced fibrosis and were more hypoxic. Furthermore, these tumors contained more CD90+ CD24+ tumor cells and more K8+ K14+ cells surrounding necrotic regions. Taken together these data suggest DDR1 loss confers a growth advantage favoring basal cell expansion via impaired luminal adhesion and enhanced basal differentiation leading to more aggressive, basal-like disease. Citation Format: Allison P. Drain, Ken Takai, Devon A. Lawson, Laurie E. Littlepage, Marcela Karpuj, Kai Kessenbrock, Annie Le, Kenichi Inoue, Valerie M. Weaver, Zena Werb. Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancer [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 LB-055.