Regulation of Apoptosis by HER2 in Breast Cancer

Abstract

HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.

Integrative pathway enrichment analysis of multivariate omics data

“…DUSP1 encodes a phosphatase signaling protein of the MAPK pathway that is over-expressed in malignant breast cancer cells and inhibits apoptotic signaling 31 . HER2 over-expression is known to suppress apoptosis in breast cancer 30 . Anti-apoptotic signaling is a hallmark of cancer and expectedly associated with worse patient prognosis.…”

Re-inforcing the cell death army in the fight against breast cancer

“…HER2 and other RTKs in breast cancer such as HER1 (also known as epidermal growth factor receptor, EGFR) are essential upstream negative regulators of the BH3-only proteins and act mainly via three pathways: PI3K-AKT, MAPK-ERK and JNK (Fig. 3) (Reginato et al, 2003;Butti et al, 2018;Carpenter and Lo, 2013). Additionally, loss of the pivotal negative regulator of the AKT pathway, phosphatase and tensin homolog (PTEN), enhances the effect of increased AKT activity and correlates with the aggressiveness of breast tumors (Datta et al, 1999;Ebbesen et al, 2016;Fournier et al, 2009;Bose et al, 2002).…”

EGFR and HER2 signaling in breast cancer brain metastasis

“…As shown in Figure 1, once phosphorylated and activated, EGFR initiates a number of downstream signaling molecules leading to cell survival, cell growth, and tumor progression (35–39). The signaling transduction cascade begins with EGFR recruitment and binding of adaptor proteins via their SH2 domains allowing for the recruitment and activation of subsequent signaling molecules, including Ras, phosphatidylinositol-3 kinase (PI-3K), phospholipase C-γ (PLC-γ), and Janus-activated kinase (JAK) (40). …”

“…Interestingly, these genes were only overexpressed in brain metastases but not in the lung metastases indicating the impact of the microenvironment on the cancer cells. Also, GSTA5, BCL2L1, and TWIST1 were shown to be regulated by AKT and MAPK which are downstream signal transducers of EGFR and HER2 (40,81,101). Although EGFR is upstream of many of these pathways, the exact link to EGFR has yet to be shown in regulating these pathways specific to brain metastasis of breast cancer.…”