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We have previously identified new kinases that are able to phosphorylate and/or modulate ERα activity via a high-throughput RNA interference screening. Amongst the most potent novel regulators was LMTK3, a previously uncharacterized molecule. We found that LMTK3 confers its anti-tumor effects predominantly via ERα-regulated signaling. Evolutionary analyses revealed LMTK3 was the only kinase that has adaptively evolved and subjected to Darwinian positive selection, an intriguing and suggestive result given the unique susceptibility of humans to ERa+ breast cancer compared to the great apes (especially for chimpanzees [Pan troglodytes], our closest living relatives). Furthermore, in a large cohort of human breast cancer patients (n = 613), LMTK3 protein levels and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapy. Finally, using an established orthotopic mouse model we demonstrated that inhibition of LMTK3 significantly reduces tumor volume and bioluminescence. Now, by performing: i) mass spectrometry (MS), ii) SILAC-based quantitative proteomics and iii) genome microarray experiments of Erα+ breast cancer cell lines (Tarn-sensitive and Tam-resistant) in the presence or absence of various treatments (Tarn, E2, ICI), we reveal certain genes, including well-defined oncogenes and tumor-suppressors that are statistically up- or down-regulated. Interestingly, amongst the newly identified LMTK3-regulated genes/proteins were targets belonging to already established signalling pathways implicated in cell survival, cytoskeletal rearrangement, transformation, and autophagy. In addition, inhibition of LMTK3 re-sensitised a Tarn treatment breast cancer mouse model, to Tarn treatment, leading to decreased tumour growth. Moreover, in patients' plasma samples, acquired LMTK3 gene amplification (copy number variation) was associated with relapse whilst receiving tamoxifen. In aggregate, these data support a role for LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine resistance in breast cancer. Further results and mechanistic data concerning LMTK3 actions will be presented, placing for the first time this new kinase in the maps of signal transduction. [ABSTRACT FROM AUTHOR]