<p>Breast cancer is the most frequently diagnosed malignancy and the second
most lethal cancer in women. Metastasis in breast cancer is invariably responsible for patient death
and is comprised of
many steps, of which proliferation in vital organs is responsible for morbidity
and mortality due to vital organ failure. Patients with the metastatic disease
are limited to chemotherapy, which non-specifically targets proliferating
cells. Despite it being initially effective, chemotherapy is associated with high
toxicity and many patients develop resistance. Thus, there is an urgent need to
characterize the biology of metastatic breast cancer to develop targeted
therapies for the late-stage disease.</p>
<p>EGFR is a member of the ErbB family of receptor tyrosine kinases, which
have particular relevance in breast tumorigenesis. Clinical studies show that
high expression levels of EGFR in the primary mammary tumors correlate with
poor prognosis and decreased survival of breast cancer patients due to
metastasis. Patient data is supported by experimental and pre-clinical studies,
which describe various signaling pathways that mediate the oncogenic effects of
EGFR, such as the MAPK, STAT3, and PI3K pathways. Despite these well-documented
roles of EGFR, clinical trials evaluating EGFR inhibitors (EGFRi) in metastatic
breast cancer have been unanimously unsuccessful in improving patient
prognosis, and the mechanisms that contribute to this intrinsic resistance are
unknown.</p>
<p>To characterize the signaling events that govern EGFR behavior in
metastatic breast cancer resistant to EGFRi, we utilized multiple pre-clinical
breast cancer progression series and patient-derived cells that display the intrinsic resistance phenomenon.
In these models, EGFR functions as a pro-apoptotic molecule whose
ligand-mediated activation results in growth inhibition and/or apoptosis of
metastatic breast cancer cells. Here we show that in the later stages of metastasis, increased nuclear translocation
of EGFR leads to increased physical access to STAT1 and STAT3 molecules
residing in the nucleus. Indeed, an EGFR mutant that is defective in
endocytosis is unable to elicit STAT1/3 phosphorylation. Additionally, specific
inhibition of nuclear EGFR function using the EGFR kinase inhibitor gefitinib
linked to a nuclear localization signal (NLS-gefitinib) prevents EGF-induced
STAT1/3 phosphorylation. Altogether, these findings implicate nuclear
localization of EGFR in downstream STAT1/3 signaling in metastatic breast
cancer.</p>
<p>Subsequently, we examined the involvement of nuclearly-activated STAT1/3
signaling in the apoptotic function of EGFR. NLS-gefitinib treatment or
genetic/pharmacologic inhibition of STAT1/3 efficiently blocks EGF-induced
apoptosis in metastatic breast cancer cells resistant to EGFRi. These findings were utilized
therapeutically by activating EGFR with EGF treatment while simultaneously
blocking the downstream proliferative MAPK:ERK1/2 pathway using the MEK1/2
inhibitor trametinib. EGF + trametinib combination preserved STAT1 signaling
while effectively blocking the MAPK pathway, thus potentiating EGF-mediated
apoptosis in metastatic breast cancer cells. Importantly, combined
administration of trametinib and EGF resulted in STAT1-mediated apoptosis of
primary mammary tumor cells, which respond to EGF in a proliferative fashion.
These data provide a novel approach of targeting metastatic breast cancer by
biasing EGFR signaling towards nuclear activation of STAT1/3 signaling
resulting in apoptosis.</p>
Our studies herein also
examined the role of STAT3 in primary mammary tumor cells overexpressing EGFR.
Depletion of STAT3 expression normalized the transformed phenotype of these
cells <i>in vitro</i> and resulted in
smaller mammary tumors <i>in vivo</i>. These
results implicate STAT3 in EGFR-driven breast tumorigenesis localized to the
mammary tissues. Further, systemic dissemination of breast cancer is associated
with activation of the JAK1/2:STAT3 signaling axis. Despite the involvement of
STAT3 in EGFR-mediated oncogenesis in the primary tumor setting, targeting
JAK1/2:STAT signaling with the JAK1/2 inhibitor ruxolitinib proved ineffective
in inhibiting the growth and invasion of metastatic cells derived from these
primary tumors. These results are in agreement with the role of STAT1/3 in
driving the pro-apoptotic function of EGFR in metastatic breast cancer cells.
Altogether, these investigations provide a plausible explanation for the
inability of JAK1/2 inhibitors to effectively target metastatic breast cancer
in clinical and experimental investigations. Further, these findings indicate
that the development of therapeutics or molecular tools that efficiently
activate STAT1/3 signaling in metastatic breast cancer may represent an
important concept for eradicating tumors resistant to targeted therapies.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/11323733 |
| Date | 05 December 2019 |
| Creators | Remah Ali (8086364) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Journal contribution |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/The_Role_of_Signal_Transducer_and_Activator_of_Transcription_1_STAT1_and_3_STAT3_in_Primary_and_Metastatic_Breast_Cancer/11323733 |
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