Page 572 - Read Online

Page 8 of 19 Cordover et al. J Cancer Metastasis Treat 2020;6:45 I http://dx.doi.org/10.20517/2394-4722.2020.101

with higher rates of recurrence and shorter rates of survival in patients with breast cancer [38,39] . Once
activated, HER2 is shown to recruit proto-oncogene Src. The constitutive activation of the Src kinase by
the overexpression of HER2 has a role in tumor progression and metastasis and is implicated in breast
[40]
cancer . Moreover, one way in which HER2 promotes metastasis is by its upregulation of the chemokine
receptor CXCR4. HER2-mediated CXCR4 expression in breast cancer is shown to be instrumental in the
movement of malignant cells to specific tissues, which contributes to poor survival rates [41,42] . In addition,
HER2 overexpression in epithelial breast cancer cells is shown to deregulate the G1/S cell cycle checkpoint.
HER2 exerts its effects on G1/S control by upregulating cyclins D1 and E and cyclin-dependent kinase
Kip1
CDK6, and by enhancing the degradation of cyclin-dependent kinase inhibitor p27 . These changes in
cell cycle progression contribute to the enhanced signaling of the PI3K/Akt and MAPK pathways .
[43]
In addition to CXCR4, HER2 interacts with several other tumor markers. For instance, estrogen receptor
(ER) and progesterone receptor (PR) are important for the prognosis and diagnosis of breast cancer. The
overexpression of ER and PR in breast cancer is associated with a better clinical outcome when compared to
tumors that overexpress HER2. Notably, ER and PR expression are inversely correlated to HER2 expression.
There are several explanations for this occurrence. For example, the hyperactivation of the MAPK pathway
in response to HER2 overexpression contributes to the downregulation of ER. Hence, the overexpression
of HER2 leads to decreased ER and PR expression and promotes oncogenesis [33,44] . Likewise, breast cancers
with HER2 amplification have been shown to overexpress the angiogenic growth factor VEGF. The HER2-
mediated upregulation of VEGF expression is associated with aggressiveness and high rates of recurrence
[45]
in HER2-positive breast cancers . Lastly, recent evidence shows that HER2 disrupts the function of the
tumor suppressor E-cadherin. E-cadherin is a transmembrane protein that mediates epithelial cell adhesion
and tissue formation. Cell-cell adhesion by E-cadherin is maintained through its interaction with β-catenin
and the cytoskeleton. HER2 disrupts the E-cadherin/β-catenin complex by binding and phosphorylating
β-catenin. This blocks the interaction between E-cadherin and β-catenin, resulting in the loss of E-cadherin
expression. As such, the loss of E-cadherin is found in over half of invasive lobular carcinomas at both the
primary tumor and metastatic sites [46-48] . Accordingly, HER2 overexpression is shown to have a prominent
role in the invasiveness of breast tumors and serves as a critical drug target.

Targeting HER2 in breast cancer
The advent of anti-HER2 therapies, along with the increase of early cancer screenings, have led to
significant improvements in the survival rates of HER2-positive breast cancer over the past two decades.
Anti-HER2 therapies, such as the monoclonal antibody trastuzumab (Herceptin) and the tyrosine kinase
inhibitor lapatinib (Tykerb), have shown to be clinically successful in treating HER2-positive breast
cancers. Nonetheless, a significant proportion of HER2-positive breast cancer patients who were treated
with trastuzumab relapse and develop metastatic disease. This indicates that tumors possess or develop
[43]
resistance to anti-HER2 therapies . In order to discern the many mechanisms of intrinsic and acquired
resistance of HER2-positive tumors, it is important to understand how trastuzumab works to inhibit
HER2. Trastuzumab is shown to downregulate HER2 by binding its extracellular domain, and to block
HER2-HER3 dimerization [49,50] . Consequently, trastuzumab exercises several anti-tumor effects in HER2-
overexpressing cells by downregulating PI3K/AKT pathway signaling along with downregulating mediators
of cell cycle progression, such as cyclin D1, and upregulating the p27 cell cycle inhibitor [51,52] .

It is critical to understand the various mechanisms behind trastuzumab resistance in order to develop novel
anti-HER2 therapies. One way in which HER2-positive cancer cells become resistant to trastuzumab is
through the constitutive activation of the PI3K/Akt/mTOR signaling cascade. Loss of function mutations
in tumor suppressor PTEN and activating mutations in PI3K lead to aggressive cell growth. These
alterations in the PI3K/Akt pathway are present in patients who have been treated with trastuzumab and
[51]
are thought to be associated with drug resistance . Another leading way that HER2 overexpressing tumor