ERBB2 and breast cancer: In HER2 positive BC, the main mechanisms of resistance to anti-HER2 agents include: impaired access to HER2 by expression of extracellular domain-truncated HER2 (p95 HER2); overexpression of Mucin 4, a mucin protein encoded by the MUC4 gene that serves as a ligand for HER2; alternative signaling from other RTKs, such as IGF-1R, other HER family members, or MET; loss of downstream controllers (PTEN, p27); and activation of downstream signaling pathways (PI3K/AKT/mTOR and MAPK pathways) [11,120].