Breast cancer is one of the most common tumors worldwide featured by heterogeneity. The expression of hormone receptors marks different breast cancer subtypes. Each type is pharmacologically treated by using molecules targeting hormone receptors, but this frequently drives to chemoresistance. Moreover, the triple negative breast cancer, which does not express hormone receptors, cannot be treated by targeting single molecules. New data suggest that the combination and intermittent therapies, where multiple agents are provided and the design regime is optimized, might be the way forward to overcome monotherapy -driven resistance, and to maximize efficacy and reduce toxicity of next generation cancer therapies. The primary aim is to develop an in vitro human breast cancer model able to predict patient pharmacological outcomes. Specific objectives are: 1) Development of a tumor on chip for multidrug screening; 2) elucidating the effect of tumor microenvironment perturbation on multidrug resistance; 3) Evaluation of the morphological and molecular effects of neoadjuvant therapy in vitro and in vivo; 4) Elucidate the role of Metformin in therapy and chemoresistance; 5) Identification of resistant cell subsets and their transcriptomic signature