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Page 6 of 14 Maisel et al. J Cancer Metastasis Treat 2019;5:7 I http://dx.doi.org/10.20517/2394-4722.2018.82

We have previously demonstrated the localization of EGFR in the nucleus when interacting with the
oncogenic adaptor glycoprotein mucin1 (MUC1). Notably, when in the presence of MUC1, EGFR is able to
bind to chromatin and act as a co-transcriptional activator by colocalizing to the transcriptional start sites
[56]
with phosphorylated RNA polymerase II . EGFR has also been shown to interact with cyclin D1 in the
nucleus and cyclin D1 expression is increased in EGFR-dependent mouse models and breast cancers [56,95-97] .
Also seen in MUC1-expressing, EGFR-driven breast cancer mouse models were high rates of lung metastases
(96 percent showing distinct pulmonary foci and the remaining 4 percent unspecified adenocarcinomas).
Alternatively, in the absence of MUC1 and nuclear EGFR, no lung metastases were observed. Taken together,
nuclear EGFR, particularly in the presence of MUC1, promotes EGFR transcriptional activity, increases
cyclin D1 expression, and drives metastasis.

To elucidate the mechanism by which MUC1 promotes nuclear localization of EGFR, we have also
demonstrated MUC1 and EGFR colocalize in EEA1-positive endosomes that are retained in the perinuclear
space and actively are trafficked away from the lysosome. This allows for signal transduction to remain
unattenuated, resulting in a MUC1-dependent increase in breast cancer cell migration rates, an effect
completely eliminated by the introduction of a retrograde trafficking inhibitor, Retro-2. Inhibiting
retrotranslocation of EGFR, even in the presence of MUC1, results in a reduced migratory phenotype
[41]
through cytoskeletal rearrangement and reduction of focal adhesion kinase (FAK)-positive structures .

EGFR is a pleiotropic signal transducer with a highly conserved activation and endocytosis pathway.
However, during cancer, a high correlation is observed between retrograde trafficking and nuclear
localization, resulting in increased metastatic events, both in vitro and in vivo.

ErbB2 receptor
ErbB2 (HER2, Neu2) is another member of the ErbB family, well-studied for its role in driving cancer
through increased cell proliferation, resistance to apoptosis, and migration. A transmembrane protein found
on the basolateral surface of cells, ErbB2 lacks the ability to bind ligands, therefore relying on other receptors
for dimerization. While EGFR is primarily driven to the lysosome as part of its endogenous trafficking,
ErbB2 is resistant to downregulation of itself or its heterodimerization partner, instead subject to rapid
[98]
recycling through CME .

ErbB2 activation is dependent upon heterodimerization with another ErbB receptor, as it lacks a ligand-
binding domain to allow for self-activation. It can also become active through extensive overexpression,
which promotes the formation of ErbB2 heterodimers responsible for enhancing the signal transduction
associated with their dimer partner, an event seen in colon, gastric, prostate, and breast cancers [59,61,99] . ErbB2
overexpression in breast cancer is so well-characterized that it is responsible for an entire classification:
HER2+; studies have shown it is amplified in more than 20 percent of breast cancer tumors, making it a
strong predictor of survival and time to relapse [100,101] .

Upregulation of ErbB2 is known to promote lymph node metastasis, as well as significantly increase
metastasis rates to the brain, liver, and lung [102] . Like all members of the ErbB family, ErbB2 can enter the
nucleus, where it can interact with promoters, including matrix metalloproteinase 16, p53-related protein
kinase, and cyclooxygenase-2 (COX-2). The COX-2 gene is known to drive metastasis in cancer cells and co-
expression of these two proteins has been reported in colon, cholangiocarcinoma, and breast cancers [103] .
[104]
Exploring further, Edwards et al. reported that prostate tumors with increased HER2 copy number also
[105]
[106]
had increased levels of COX-2 expression while Thorat et al. and Glynn et al. demonstrated that COX-2
levels are highest (if not statistically significant) in HER2+ breast cancer (vs. luminal A/B and triple negative
breast cancers) and that positive COX-2 expression in HER2+ patients is directly correlated to increased
phosphorylation of AKT and poor survival outcomes [104-106] .