Despite many efforts, no effective therapy exists to overcome breast cancer endocrine resistance. The major drawback is that most of the known oncogenes cannot be matched with potent and safe drugs; for the few with inhibitors, clinical responses are limited and transient due to rapid development of escape pathways not yet understood. It is thus critical to uncover both the missing targets in the unknown survival pathways and the drugs that can tackle this disease. In this study, we apply a unique integrative analysis that identifies key drug targets from the complex cancer signaling network by combining genomic/pharmacological information with cancer-gene concept signature (ConSig). This analysis has revealed a new target, Nemo-like kinase (NLK), which is amplified and/or overexpressed in ~30% of breast cancers. We have shown that NLK drives more aggressive phenotypes, endows endocrine-resistant growth, and predicts worse outcome in tamoxifen- treated patients. Further investigation suggests that NLK modulates multiple key molecules in the estrogen receptor (ER) pathway or involved in endocrine resistance, such as STAT3, FOXOs, AKT, ERK, and p27. More important, a potent NLK inhibitor has been identified which effectively sensitizes breast cancer cells to tamoxifen. NLK can be activated by multiple growth factors distinct from the well-known breast cancer pathways. We thus hypothesize that this protein may be a hub molecule that drives previously uncharacterized survival signaling in a considerable subset of intractable breast tumors. As the safety of the NLK inhibitor has already been established in other clinical trials, it holds an immediate and high potential to transform th care of breast cancer patients. The following studies are proposed to test the hypothesis: Aim 1 will investigate how NLK crosstalks with the ER pathway to restore ER activity, and how NLK engages ER-independent signaling to provide alternative survival and invasive stimuli in the context of endocrine therapy. Aim 2 will establish NLK function in tumor formation and hormone resistance using transplanted NLK inducible genetic perturbation models. The therapeutic value of the NLK inhibitor in sensitizing endocrine therapy will be assessed on mice bearing NLK-high ER+ xenograft breast tumors. Aim 3 will investigate the correlation of NLK protein with the response or relapse of breast cancer patients treated with tamoxifen or aromatase inhibitors. This study will also establish an NLK immunohistochemistry (IHC) assay to select patients for NLK-targeted therapy. We expect that these studies will confirm the role of NLK in breast cancer endocrine resistance, elucidate the NLK-driven mechanisms to promote cancer cell survival, validate the NLK inhibitor as a sensitizing agent to endocrine therapy, and establish theNLK IHC as a predictive assay for precision medicine. This individualized targeted-therapy would benefit a considerable population of breast cancer patients that have developed or are likely to develop endocrine resistance.