The role of wnt10b in a translational model for triple-negative breast cancer

In 2010 over 200,000 new cases of invasive breast cancer were diagnosed in the United States. Based on DNA microarray expression profiling, human breast tumors have been divided into five subtypes: Luminal A, Luminal B, ERBB2/HER2, normal breast-like and basal-like/triple negative (TN). TN tumors are defined by the absence of Estrogen (ER), Progesterone (PR), and HER2 expression. Patients diagnosed with TN breast cancer have a poor prognosis due to a highly metastatic phenotype and resistance to most therapeutics developed. Wnt/b-catenin signaling has been suggested to be overexpressed in TN breast cancer. However, evidence for mutations in components of the Wnt/b-catenin pathway in breast cancer is extremely rare. Wnt-ligands are shown to be amplified and over expressed in human breast cancer. We hypothesize that in particularly TN breast cancer is caused by over expression of a Wnt-ligand triggering activation of the Wnt/b-catenin cascade.  To test this hypothesis we utilize MMTV-Wnt10b-IRES-LacZ (Wnt10b^LacZ) transgenic mice to model TN breast cancer. Using expression profiling, FACS and cell biology/stem cells assays we show that WNT10B activates canonical b-catenin signaling leading to up-regulation of self-renewal markers and specific cyclins, which induces proliferation of breast tumor initiating cells. We illustrate that an inhibitor of the Wnt/b-catenin pathway blocks proliferation and self-renewal in Wnt10b^LacZ primary mouse tumor cells and in human TN breast cancer cell lines, respectively. The modeling of TN human breast cancer utilizing the Wnt10b-oncogene may provide novel insights into a therapeutic regiment that can be translated to treat TN patients.