POSSIBLE CBFbeta-RUNX1 REGULATION OF R-SPONDIN 3 EXPRESSION IN BREAST CANCER

FELCHER, C. M.; TOCCI, J. M.; GARCÍA SOLÁ, M. E.; CASTILLA, L. H.; KORDON, E. C.

Bariloche

Simposio; Fourth South American Spring Symposium in Signal Transduction and Molecular Medicine; 2018

R-spondin 3 (RSPO3) is a positive modulator of the Wnt pathway, which is essentialto several developmental processes, while its de-regulation underlies a wide range ofpathologies including cancer. We recently demonstrated that RSPO3 is expressed inthe basal stem cell-enriched compartment of the mouse mammary gland and that itplays a relevant role in epithelial-mesenchymal transition as well as in mammarytumor progression. We found that RSPO3 is expressed in human breast cancers,particularly in the basal-subtype, which lacks efficient therapeutic options. Afteranalyzing samples from 75 patients with ductal infiltrating breast carcinomas, wefound that most of them showed positive immunoreactivity for RSPO3 (70%). Thereis limited understanding of the factors regulating RSPO3 expression, particularly inmammary cells. Previous reports suggest the potential involvement of the RUNX(RUNX1, RUNX2 and RUNX3) transcription factors, which form heterodimerictranscription factors by binding CBFβ. The genes coding for RUNX1 and CBFβ arefrequently mutated in human leukemias and, recently, it was observed that RUNXproteins also play important roles in epithelial and breast cancer. Interestingly, wehave determined that RSPO3 co-expresses with RUNXs by analysing the expressiondata of The Cancer Genome Atlas (TCGA) Network from 1985 human breastcarcinoma samples. Besides, our results show that CBFβ inhibitors decrease RSPO3levels in the breast cancer cell line HCC1143. Importantly, previously reported dataindicate that these small molecules inhibit HCC1143 colony formation. Therefore,although further studies are required to determine the relevance of RUNX-CBFβ onRSPO3 expression in vivo and its impact on breast cancer development, our resultssuggest this regulation might be a new molecular target for therapeutic modulationin breast cancer control.