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Tian et al. EMT drives anti-estrogen resistance in breast cancer

programs are more commonly associated with basal- mechanisms whereby TGF-β and EMT programs
like/TNBCs, we show herein that luminal A (e.g. MCF- elicit extranuclear exclusion of ER-α; they also need
7) and luminal B (e.g. BT474) breast cancer cells not to explore the linkages between EMT programs and
only undergo EMT in response to TGF-β, but that they ER-α mutations in regulating metastasis and disease
also exhibit diminished sensitivity to tamoxifen that recurrence.
results from the: (1) upregulated expression of EGFR
and IGF1R, which interact physically with ER-α; (2) As mentioned previously, EMT programs are closely
hyperactivation states of MAP kinases (e.g. ERK1/2 associated with the acquisition of drug-resistant
and p38 MAPK); and (3) extranuclear exclusion phenotypes. [4,22,23] Indeed, tamoxifen-resistant MCF-7
and nongenomic functions of ER-α. Importantly, the cells exhibit post-EMT morphologies (i.e. mesenchymal-/
enhanced tumorigenic activities displayed by post- fibroblastoid-like) that reflect a loss of E-cadherin
EMT cells were readily reversed by co-administration of expression and a gain of β-catenin signaling, events
tamoxifen with small molecule inhibitors against either that were readily reversed following administration of
[34]
TβR-I (i.e. TβR-I inhibitor II), IGF1R (i.e. AG1024), EGFR inhibitors. A similar dependence upon EMT
EGFR (i.e. AG1478), or MEK1/2 (i.e. U0126), thereby programs was observed in pancreatic cancers as they
laying the foundation for future investigations related acquired resistance to gemcitabine, 5-fluorouracil,
to how inactivating EMT programs can be harnessed and cisplatin, a reaction driven by the upregulated
to improve the clinical outcomes of breast cancer expression of Zeb1. Indeed, genetic inactivation of
patients. Zeb1 in post-EMT, chemoresistant pancreatic cancer
cells was sufficient to induce a mesenchymal-to-
Several studies previously implicated the nongenomic epithelial transition (MET) that reinstated cellular
actions of ER-α in promoting tamoxifen resistance sensitivity to conventional chemotherapeutic agents.
[35]
and disease progression. [9,11-13,32] For instance, the Likewise, resistance to EGFR and FGFR3 inhibitors in
aberrant expression of truncated MTA1 mutants that cancers of the bladder coincides with their completion
remain competent to bind ER-α and sequester it in of EMT programs engendered by the loss of miR-200
the cytoplasm clearly contribute to the generation of family member expression. Importantly, restoring miR-
nongenomic ER-α activity. Indeed, MTA1 expression 200 expression in post-EMT bladder cancer cells not
[14]
inactivates hormone-induced nuclear translocation of only induced their undertaking of MET programs, but
ER-α, an event that enhances tumor progression and also reactivated their sensitivity to EGFR and FGFR3
correlates with a loss of ER-α in the nucleus. Along inhibitors. Our studies herein reinforce the central
[14]
[36]
these lines, ER-α expression and activity also require importance of EMT programs to elicit chemoresistance
interactions with growth factor signaling systems in developing and recurring cancers, particularly
to enable luminal breast cancer cells to become those arising in the breast. Moreover, we established
insensitive to ER-α modulating agents. For instance, TGF-β and EMT programs as drivers of tamoxifen
tamoxifen-resistant MCF-7 cells house cytoplasmic resistance and nongenomic ER-α signaling in luminal
complexes comprised of ER-α, EGFR, and Src that breast cancers; we also provide a new and potentially
elicit hyperactivation of MAP kinases by either EGF or impactful approach to eliminate tamoxifen-resistant,
estradiol. Consequently, targeted inactivation of either post-EMT breast cancer cells through the combined
Src, EGFR, or MAPK not only restores ER-α to the administration of tamoxifen with inhibitors against
nucleus, but also reestablishes the antitumor activities either TβR-I, EGFR, IGF1R, or MEK1/2, thereby
of tamoxifen in ER-positive tumors. [12,32] Besides its restoring the effectiveness of anti-hormone therapies
ability to bind EGFR, ER-α also complexes with the in ER-positive tumors.
IGF1R at the cell membrane, an interaction involving
the adaptor protein Shc. [31,32] Moreover, tamoxifen- DECLARATIONS
resistant breast cancer cells can also undergo RTK
switching as a means to evade targeted inactivation of Authors’ contributions
either EGFR or IGF1R, thereby preserving nongenomic Conceived and designed the study: M. Tian, W.P.
ER-α signaling. It should be noted that RTK switching Schiemann
[12]
is a mechanism associated TGF-β and its stimulation Performed molecular and cellular analyses: M. Tian
of EMT programs. Given the parallels between the Performed literature search and prepared the
[33]
aforementioned findings and those presented herein, manuscript: M. Tian
it is tempting to speculate that EMT programs function Revised the manuscript: W.P. Schiemann
as essential drivers of nongenomic ER-α signaling and
disease progression in luminal breast cancer cells. Financial support and sponsorship
Future studies need to determine the exact molecular Research support was provided in part by the National
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ August 21, 2017 159