Page 297 - Read Online

Lei et al. J Cancer Metastasis Treat 2019;5:38 I http://dx.doi.org/10.20517/2394-4722.2019.12 Page 13 of 16

The underlying mechanism of how ESR1 fusions arise remains unclear. However, as mentioned earlier,
DSBs mediated by recruitment of TOP2B to ER transcriptional complexes may contribute to formation of
ESR1 fusion genes, and therefore TOP2B could potentially be an attractive therapeutic target to prevent the
formation of ESR1 fusion events. More studies are required to test this hypothesis. Daunorubicin, an FDA-
approved chemotherapeutic drug indicated for treating leukemia, targets TOP2B, however, this agent is very
toxic. Developing less toxic agents that target TOP2B may represent a therapeutic strategy to prevent ESR1
translocation events and deserves further study in the context of ER+ breast cancer.

Therapeutic targeting these aberrant forms of ER have shown promise in pre-clinical experimental models
with more studies required to translate such findings to the clinic. Collectively, these studies deepen our
understanding of how ESR1 alterations trigger breast cancer to become lethal metastatic disease and will
guide development of therapeutic strategies to treat a subset of patients with tumors that contains these ESR1
alterations.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception: Lei JT, Gou X, Seker S
Provided initial drafts of the work: Lei JT, Gou X, Seker S
Revising the work critically for important intellectual content: Lei JT, Ellis MJ
Final approval of the version: Lei JT, Ellis MJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by a Susan G. Komen Promise Grant (PG12220321) to Ellis MJ; a Cancer
Prevention Institute of Texas (CPRIT) Recruitment of Established Investigators Award (RR140033) to
Ellis MJ; a Breast Cancer Research Foundation Grant (BCRF ELFF-16-003) to Ellis MJ; and by a National
Institutes of Health Training Grant (T32-GM088129) to Lei JT.

Conflicts of interest
Ellis MJ received consulting fees from Abbvie, Sermonix, Pfizer, AstraZeneca, Celgene, NanoString, Puma,
and Novartis, and is an equity stockholder, consultant, and Board Director member of BioClassifier, and
inventor on a patent for the Breast PAM50 assay.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.

REFERENCES
1. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding
assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999;17:1474-81.
2. Joel PB, Traish AM, Lannigan DA. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Mol
Endocrinol 1995;9:1041-52.
3. Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS. Phosphorylation of the human estrogen receptor. Identification of hormone-