Dissecting the Transcriptional Network of WNT10B/Beta-catenin Signaling in Triple-Negative Breast Cancer

Breast cancer is the second leading cause of death among women. Of the five subgroups, basal-like/triple-negative (TN) breast cancer is the most aggressive and malignant subtype.  This subgroup is classified by its lack of expression of estrogen receptor (ER^-), progesterone receptor (PR), and ERBB2/HER2. A therapeutic regimen for TN breast cancer remains a major challenge in the clinics. We found that Wnt10B/β-catenin signaling is deregulated in mouse and human TN-breast cancer and that a β-catenin inhibitor could specifically block proliferation of TN tumor cells. The inhibitor disrupts the protein-protein interaction between β-catenin and its transcriptional co-activator CBP implying that b-catenin now can either bind to different transcriptional regulators or translocate into the cytoplasm. In this study we want to unravel the mechanisms of how the inhibitor treatment affects b-catenin. We hypothesize that upon disruption of the β-catenin/CBP complex β-catenin forms new protein interactions, possibly with p300 and  other transcriptional regulators, e.g. members of the Lef/Tcf family. To address these questions immuno-precipitation and Western blot analysis is used to extract b-catenin interaction partners. We observed a reduction in total β-catenin protein levels after inhibitor treatment, suggesting reduced expression of the β-catenin protein or release of b-catenin for degradation. Moreover, the b-catenin/CBP complex is predominant in highly proliferating cells but strongly decreased in growth-arrested cells. In conclusion, we want to gain new insight into the transcriptional network of WNT10B/b-catenin signaling using a biochemical approach. Our results could potentially facilitate the development of therapies for TN breast cancer and other Wnt-related disease.