RSPO3, a positive WNT pathway modulator induces mesenchymal features in mammary cells and is differentially expressed by the basal-progenitor population and triple-negative breast cancers

GARCÍA SOLÁ M; COSO O.; MEISS RP; FELCHER C; ZIMBERLIN MN; ABBA MC; TOCCI JM.; GODDIO MV; ANABELLA SREBROW; KORDON E

Mar del Plata

Congreso; Reunión Anual SAIC; 2017

Abstract: Breast cancer is a leading cause of death among women worldwide. R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance canonical and non-canonical Wnt signaling pathways. Due to their Wnt-potentiating activity, RSPOs have been postulated as stem cell growth factors and are implicated in diverse processes like embryonic development, tissue differentiation and human diseases including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. We identified MMTV insertion sites close to Rspo3 gene, promoting its over- expression and the consequent tumor formation. There- fore, our goal was to investigate the biological function of RSPO3 in normal and tumor mammary cells. Recently, we found that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands whereas it is absent from committed mature luminal cells, in which exogenous RSPO3 impairs lactogenic differentiation. In addition, RSPO3 knockdown in bas- al-like mouse mammary tumor cells reduces canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Importantly, RSPO3 overexpression, which is associated with leucine-rich repeat-containing G-protein coupled receptors 4, 5 and 6 (LGR4-6) levels, highly correlates with the basal-like subtype among breast cancer patients, particularly with triple-negative claudin-low tumors. Thus, we identified RSPO3 as a novel key modulator of breast cancer development that may become a potential target for treatment of the basal subtype which lacks efficient therapeutic options to date.