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Stem Cell Reports. 2018 Nov 13;11(5):1040-1050. doi: 10.1016/j.stemcr.2018.09.008. Epub 2018 Oct 18.

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

Author information

1
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Cell Polarity, Cell Signaling and Cancer'- Equipe Labellisée Ligue Contre le Cancer, Marseille, France.
2
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Predictive Oncology'- Equipe Labellisée Ligue Contre le Cancer, Marseille, France.
3
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Epithelial Stem Cells and Cancer', Marseille, France.
4
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, TrGET Pre-clinical Assay Platform, Marseille, France.
5
Centre de Recherche en Cancérologie de Marseille, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, 'Cell Polarity, Cell Signaling and Cancer'- Equipe Labellisée Ligue Contre le Cancer, Marseille, France. Electronic address: marie-josee.santoni@inserm.fr.

Abstract

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.

KEYWORDS:

LANO/LRRC1; SCRIB; Wnt/β-catenin; breast cancer; stem cell; tumor suppressor

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