fig5

Figure 5. Bi-directional cross-talk with HER2 and nuclear receptors. While ER signaling is the dominant driver of cell proliferation and survival in breast cancer, alternate receptors such as PgR and AR can also influence HER2-mediated cell proliferation in breast cancer. Direct inhibitors against ER (tamoxifen or fulvestrant) or AR (enzalutamide, bicalutamide, or enobosarm) can work in concert with lapatinib to directly target HER2 signaling and attenuate cell cycle regulation. Combining lapatinib and nuclear receptor inhibitors with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) can synergistically attenuate HER2-mediated cell growth. Images were created using Biorender.com. AR: androgen receptor; CDK 4/6: cyclin-dependent kinase 4/6; DHT: dihydrotestosterone; EGFR: epidermal growth factor receptor; E2: estradiol/estrogen; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; IGF-1R: insulin-like growth factor 1 receptor; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; PgR: progesterone; Rb: retinoblastoma protein; T: testosterone; TSC 1/2: TSC complex subunit 1/2; ERE: estrogen response element; ARE: androgen response element; T-DM1: trastuzumab emtansine DM1; PR: progesterone receptor