HIC1 Deletion Promotes Breast Cancer Progression By Activating Tumor Cell/fibroblast Crosstalk

Breast cancer(BrCa)is the most frequently diagnosed malignant tumor in women worldwide and represents the main cause of cancer-related death.Although systematic therapeutic approaches have decreased cancer-specific mortality,BrCa is still associated with high rates of cancer recurrence and metastasis.Therefore,exploring the molecular mechanism underlying BrCa progression may be beneficial for diagnosis and treatment of the disease.Here,we found that conditional deletion of hypermethylated in cancer 1(HIC1)in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation.Meanwhile,coculture experiment revealed that HIC1-deleted BrCa cells could induce activation of mammary fibroblasts.Moreover,RT-qPCR,ELISA,Luciferase and ChIP assays identified CXCL14,a chemokine,was a direct target of HIC1.CXCL14 secreted by HIC1-deleted BrCa cells bound to its novel cognate receptor GPR85 on fibroblasts and was responsible for activating them via the Erk1/2,Akt,and neddylation pathways.Furthermore,using cytokines array assays,we found that the activated fibroblasts secreted more chemokine CCL17 promoting BrCa progression via induction of the epithelial–mesenchymal transition(EMT)by CCL17/CCR4 axis.Clinically,HIC1-CXCL14-CCL17 loop was associated with malignant progression of BrCa through detection of breast tissue microarrays.Therefore,the crosstalk between HIC1-deleted BrCa cells and mammary fibroblasts might play a critical role in BrCa development.Taken together,exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic marker of breast tumor and providing the more effective treatment strategy.