TSC2 and breast cancer: Recently, cyclin D1/CDK4 is shown to mediate targeted therapy resistance in HER2+ breast cancer [49], while CDK4/6 inhibition reduces TSC2 phosphorylation, mTORC1 activity and cell proliferation, increases tumor cell dependence on EGFR family kinase signaling [50] and provides a potent adjunct to HER2-targeted therapies in preclinical breast cancer models [51].