RSPO3, A POSITIVE WNT PATHWAY MODULATOR, INDUCES MESENCHYMAL FEATURES IN MAMMA- RY CELLS AND IS DIFFERENTIALLY EXPRESSED BY THE BASAL-PROGENITOR SUBPOPULATION AND TRIPLE-NEGATIVE BREAST CANCERS.

TOCCI JM; FELCHER CM; GARCIA-SOLA ME; ABBA MC; GODDIO MV; ZIMBERLIN, MARÍA NOEL; COSO OA; SREBROW, ANABELLA; MEISS, ROBERTO P; KORDON E

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Abstract: Breast cancer is a leading cause of death amongwomen worldwide. R-spondin3 (RSPO3) is a memberof a family of secreted proteins that enhance canonicaland non-canonical Wnt signaling pathways. Due to theirWnt-potentiating activity, RSPOs have been postulatedas stem cell growth factors and are implicated in diverseprocesses like embryonic development, tissue differen-tiation and human diseases including cancer. However,the role of RSPO3 in mammary gland and breast can-cer development remains unclear. We identified MMTVinsertion sites close to Rspo3 gene, promoting its over-expression and the consequent tumor formation. There-fore, our goal was to investigate the biological function ofRSPO3 in normal and tumor mammary cells. Recently,we found that RSPO3 is expressed in the basal stemcell-enriched compartment of normal mouse mammaryglands whereas it is absent from committed mature lumi-nal cells, in which exogenous RSPO3 impairs lactogenicdifferentiation. In addition, RSPO3 knockdown in bas-al-like mouse mammary tumor cells reduces canonicalWnt signaling, epithelial-to-mesenchymal transition-likefeatures, migration capacity, and tumor formation in vivo.Importantly, RSPO3 overexpression, which is associatedwith leucine-rich repeat-containing G-protein coupled re-ceptors 4, 5 and 6 (LGR4-6) levels, highly correlates withthe basal-like subtype among breast cancer patients,particularly with triple-negative claudin-low tumors. Thus,we identified RSPO3 as a novel key modulator of breastcancer development that may become a potential targetfor treatment of the basal subtype which lacks efficienttherapeutic options to date.