Breast cancer is diagnosed in ~1.4 million women worldwide and ~500,000 lives are lost to the disease annually. Patients may do well after surgery and initial treatment, but drug resistant and fatal metastases often develop. Improved treatment options are urgently needed. The connecting thread of this project is the identification of epigenetic drivers of breast cell fate, tumor heterogeneity and metastasis.Tumor heterogeneity impinges on prognosis, response to therapy, and metastasis and is one of the most important and clinically relevant areas of cancer research. Tumor heterogeneity results from genetic and epigenetic alterations that enhance the plasticity and fitness of cancer cells in the face of hurdles like the metastatic cascade and anti-cancer therapies. Unfortunately, the driving molecular mechanisms remain unclear, particularly the potential interplay between signalling pathways and epigenetic programs.This interdisciplinary project uses pathophysiologically relevant models and state-of-the-art technologies to identify molecular mechanisms underlying crosstalk between key signalling pathways and epigenetic programs in the normal and neoplastic breast. We hypothesize that interfering with these programs will decrease tumor heterogeneity.We will address the effects of:- SHP2/ERK signalling on the epigenetic programs of tumor-initiating cells (Aim 1)- PI3K pathway hyperactivation on the epigenetic programs underpinning cell plasticity (Aim 2)- Epigenetic regulators on normal mammary cell self-renewal and on metastasis (Aim 3)By investigating the integrated effects of key signalling pathways and epigenetic programs in normal and neoplastic breast, this multipronged project will identify and validate mechanisms of cell plasticity. The derived mechanistic understanding will generate means to interfere with tumor heterogeneity and thus improve the efficacy of anti-cancer therapies and ultimately the clinical outcome for patients with breast cancer.