Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer

Table 1

Proposed mechanisms of action of HER2-targeted therapies.

Drug	Trastuzumab	Lapatinib	Pertuzumab
Effects on HER2 expression	Potential down-regulation of HER2 from the cell surface; blocks cleavage of HER2 ECD, suppressing formation of p95HER2	Accumulation/increased expression of total HER2 at the cell surface
Effects on dimerization	Potentially partial disruption of dimerization		Sterically hinders interactions of HER2 with other receptors
Effects on downstream signaling	Inhibits PI3K and MAPK signaling	Inhibits PI3K and MAPK signaling	Inhibits PI3K and MAPK signaling
Immune effects	Stimulates ADCC		Stimulates ADCC
Effects on cell cycle regulators	Induction of p27, p21; cdk2 inhibition	Induction of p27; cdk2 inhibition	Induction of p27, p21; cdk2 inhibition
Effects on apoptotic regulators	Down-regulation of Bcl-2, surviving, and Mcl-1	Down-regulation of survivin and Mcl-1; up-regulation of BIM and Fox03a	Induces apoptosis, although mechanisms are unknown