We build on our previous hypotheses/work to investigate and unravel how MSK1 contributes to BCa dormancy. We will determine how chromatin is organized within dormant tumour cells (DTCs), focusing on histone H3 to map genomic and transcription changes associated with metastatic escape from non-adaptive, anti-tumor immune activities. We will test the metastasis cascade of events to pinpoint how to therapeutically intervene in crosstalk between signalling pathways and/or the epigenetic regulations that support metastatic escape. We will characterize, at the genetic, biochemical, and cellular levels, whether MSK1 in DTC cells controls mediators of the non-adaptive immune response. To establish the contribution of MSK1 in attenuating the NK functions in metastatic cells, we will use both stable gain-of-function (gene overexpression) and loss-of-function (gene knockdown/knockout via shRNA and CRISPR/Cas9). We will test the metastatic activities of these transfectants with in vitro experiments as well as inoculation into immunocompromised mice of various backgrounds with immune deficiencies, including Balb/c Nude athymic mice (FOXN1nu) that retain functional innate system, and the more immune compromised NOD/SCID gamma mice with neither adaptive nor innate immunity.