The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/β-Catenin Signaling

Abstract

Summary: Tumor initiation, progression, and therapeutic resistance have been proposed to originate from a subset of tumor cells, cancer stem cells (CSCs). However, the current understanding of the mechanisms involved in their self-renewal and tumor initiation capacity remains limited. Here, we report that expression of LANO/LRRC1, the vertebrate paralog of SCRIB tumor suppressor, is associated with a stem cell signature in normal and tumoral mammary epithelia. Through in vitro and in vivo experiments including a Lano/Lrrc1 knockout mouse model, we demonstrate its involvement in the regulation of breast CSC (bCSC) fate. Mechanistically, we demonstrate that Lano/LRRC1-depleted cells secrete increased levels of WNT ligands, which act in a paracrine manner to positively deregulate the WNT/β-catenin pathway in bCSCs. In addition to describing the first function of LANO/LRRC1, our results suggest that its expression level could be used as a biomarker to stratify breast cancer patients who could benefit from WNT/β-catenin signaling inhibitors. : In this article, Santoni and colleagues report that expression of LANO/LRRC1, the paralog of SCRIB tumor suppressor, is associated with normal and tumoral mammary stem cell signature. Lano/LRRC1 represses expansion of cancer stem cell pool through inhibition of WNT ligand secretion and related WNT/β-catenin pathway activation. LANO/LRRC1 might have theranostic value to steer patient treatment by WNT/β-catenin signaling inhibitors. Keywords: breast cancer, stem cell, LANO/LRRC1, SCRIB, Wnt/β-catenin, tumor suppressor