Abstract PR2: A genetic screen for novel determinants of anoikis resistance identifies PVRL4

Abstract

Abstract Tumor cells develop resistance to detachment-induced cell death, known as anoikis, and rely on it for survival throughout the course of disease progression. Through a gain-of-function genetic screen for novel determinants of anoikis resistance, we found that PVRL4 (poliovirus receptor-like 4) promotes anchorage-independent colony formation in HMECs (human mammary epithelial cells). PVRL4 belongs to a family of transmembrane proteins involved in early stages of adherens junction formation. PVRL4 is expressed in focally amplified in breast cancer and positively correlates with spread of cancer into lymph nodes and poor survival prognosis. PVRL4 promoted cell aggregation of HMECs, and induction of cell aggregation was sufficient to promote anchorage-independent colony formation. Cell aggregation and transformation induced by PVRL4 were abrogated in presence of a monoclonal antibody targeting its extracellular region. Furthermore, stable depletion of PVRL4 in breast cancer cells inhibited spontaneous cell aggregation and anchorage-independent growth. Taken together, our findings demonstrate the key role of PVRL4 in cellular transformation and suggest that it functions via promoting cell aggregation. Cancer cells are known to exhibit increased cell aggregation; moreover, increased cell aggregation correlates with metastatic potential. Multicellular clusters of cancer cells are present among circulating tumor cells (CTCs) blood from cancer patients and as well as in mouse cancer models. Promotion of survival in the absence of attachment via inducing cell aggregation may therefore provide a unique advantage for CTC survival in the bloodstream and spread into distant organs. Finally, inhibition of PVRL4-induced aggregation and anchorage-independence by monoclonal antibodies demonstrates a potential new therapeutic strategy against breast cancer. This abstract is also presented as Poster B5. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR2.