Tumorigenesis involves the accumulation of genetic aberrations, leading to the emergence of distinct clonal subpopulations. Studies that have tracked the evolution of genetic events within and between these clonal populations have provided deep insights into the process of tumorigenesis and response to therapy. Despite these advances, the process of metastasis, which is responsible for over 90% of cancer-related deaths, remains poorly understood. The majority of studies that compare genetic aberrations between the primary tumor and metastases find few alterations that are unique to the metastatic clone. Indeed, there are no known recurrent genetic drivers of metastasis. In contrast to primary tumor initiation and establishment, my own future research directions hypothesize that the process of metastasis does not rely on the further acquisition of novel genetic alterations beyond those needed to form primary tumor cells, but is instead driven by alterations to the chromatin landscape, presenting itself in the form of cellular plasticity and a reprogrammed cell state. We have uncovered evidence of a luminal- to-basal transition (LBT) in breast cancers of the luminal B molecular subtype. The LBT is essential for tumor progression as tumors that do not exhibit this plasticity show attenuated metastatic ability and are more sensitive to chemotherapy. Based on these data we hypothesize that the acquisition of tumor cell plasticity that allows breast cancer cells to stray from their lineage-of-origin is an essential first step to initiating the metastatic cascade and disease progression. This increased plasticity likely propels cells into a state that is highly adaptive to new habitats and responsive to interactions with components of the tumor microenvironment, all of which are critical to the process of metastasis. We propose to test this by elucidating the effects of the LBT in luminal B breast cancers by assessing the stability of the cells that undergo the transition, their tumor-initiating capacity and metastatic potential (aim 1). We will further uncover the mechanisms driving the transition by studying the role of Sox4 in the emergence of the basal cells of luminal origin, tracking its expression and determining its genome-wide occupancy to reveal changes to its target gene repertoire during metastatic progression (aim 2). We then propose to test the principle of tumor differentiation as a potential adjuvant to chemotherapy by either combinatorial activation of Gαs R201C/fl and chemotherapy administration, or by sequential activation of Gαs R201C/fl followed by chemotherapy administration.