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Figure 2. Her2 signaling: HER2 is a member of the HER/EGFR family of RTKs. HER2 signaling has important roles in regulating normal
cell function. However, its dysregulation is often implicated in cancer. HER2 can homodimerize with itself or heterodimerize with the
other members of the HER family. Overexpression of HER2 can lead to the overactivation of the MAPK/ERK and PI3K/AKT/mTOR
pathways, leading to uncontrolled cell growth and evasion of apoptosis. HER: human epidermal growth factor receptor; EGFR: epidermal
growth factor receptor; RTK: receptor tyrosine kinase; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated
kinases; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin

ligands, HER2 is activated by homodimerization or heterodimerization with HER1, HER3, or HER4 [33,34]
[Figure 2].

The signaling pathways regulated by the HER receptors have important roles in responding to extracellular
signals and in turn regulating normal cell function. Improper regulation of the HER receptors, especially
HER1 and HER2, can be associated with cancer. In healthy cells, HER2 activation triggers signaling
pathways that control normal cell growth, differentiation, motility, and adhesion. Overexpression of HER2
leads to the over-activation of downstream pathways, including the PI3K/Akt/mTOR and MAPK/ERK
[35]
signaling cascades, which are known to be involved in malignant transformation . The overexpression of
HER2 signaling is shown to promote the loss of cell adhesion and polarity, defining features of epithelial
cancers [36,37] . As such, HER2 dysregulation is associated with ovarian cancer, gastric cancer, and perhaps
most notably, breast cancer.

HER2 in breast cancer
Breast cancer is the most common type of cancer among women in the United States, and 20-30% of breast
cancers are thought to be HER2-positive. Amplification of the HER2 gene in breast cancer is associated
with invasiveness, large tumor size, and late clinical stage. HER2 overexpression is also associated