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

CARLA WELCHER; JOHANNA TOCCI; MARTIN GARCIA SOLA; LUCIO CASTILLA; EDITH C KORDON

Simposio; SISTAM 2018; 2018

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