TY - JOUR
T1 - Development and characterization of novel endoxifen-resistant breast cancer cell lines highlight numerous differences from tamoxifen-resistant models
AU - Jones, Calley J.
AU - Subramaniam, Malayannan
AU - Emch, Michael J.
AU - Bruinsma, Elizabeth S.
AU - Ingle, James N.
AU - Goetz, Matthew P.
AU - Hawse, John R.
N1 - Funding Information:
C.J. Jones reports grants from NIH and Eisenberg Foundation during the conduct of the study; personal fees from Broad Institute of MIT and Harvard outside the submitted work. J.N. Ingle reports grants from NCI and Eisenberg Foundation during the conduct of the study. M.P. Goetz reports other (consulting fees to institution) from Eagle Pharmaceuticals, Lilly, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, and Biotheranostics; grants from Pfizer, Sermonix, and Lilly outside the submitted work. J.R. Hawse reports grants from NIH and Eisenberg Foundation during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
Research reported in this publication was supported by the NCI of the NIH through the Mayo Clinic Breast Cancer SPORE Grant P50CA116201 (to J.N. Ingle, M.P. Goetz, and J.R. Hawse); the Eisenberg Foundation (to J.R. Hawse); and the Mayo Clinic Graduate School of Biomedical Sciences (to C.J. Jones and M.J. Emch).
Publisher Copyright:
2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - Despite the availability of drugs that target ERa-positive breast cancer, resistance commonly occurs, resulting in relapse, metastasis, and death. Tamoxifen remains the most commonly-prescribed endocrine therapy worldwide, and “tamoxifen resistance” has been extensively studied. However, little consideration has been given to the role of endoxifen, the most abundant active tamoxifen metabolite detected in patients, in driving resistance mechanisms. Endoxifen functions differently from the parent drug and other primary metabolites, including 4-hydroxy-tamoxifen (4HT). Many studies have shown that patients who extensively metabolize tamoxifen into endoxifen have superior outcomes relative to patients who do not, supporting a primary role for endoxifen in driving tamoxifen responses. Therefore, “tamoxifen resistance” may be better modeled by “endoxifen resistance” for some patients. Here, we report the development of novel endoxifen-resistant breast cancer cell lines and have extensively compared these models to 4HT and fulvestrant (ICI)-resistant models. Endoxifen-resistant cells were phenotypically and molecularly distinct from 4HT-resistant cells and more closely resembled ICI-resistant cells overall. Specifically, endoxifen resistance was associated with ERa and PR loss, estrogen insensitivity, unique gene signatures, and striking resistance to most FDA-approved second- and third-line therapies. Given these findings, and the importance of endoxifen in the efficacy of tamoxifen therapy, our data indicate that endoxifen-resistant models may be more clinically relevant than existing models and suggest that a better understanding of endoxifen resistance could substantially improve patient care. Implications: Here we report on the development and characterization of the first endoxifen-resistant models and demonstrate that endoxifen resistance may better model tamoxifen resistance in a subset of patients.
AB - Despite the availability of drugs that target ERa-positive breast cancer, resistance commonly occurs, resulting in relapse, metastasis, and death. Tamoxifen remains the most commonly-prescribed endocrine therapy worldwide, and “tamoxifen resistance” has been extensively studied. However, little consideration has been given to the role of endoxifen, the most abundant active tamoxifen metabolite detected in patients, in driving resistance mechanisms. Endoxifen functions differently from the parent drug and other primary metabolites, including 4-hydroxy-tamoxifen (4HT). Many studies have shown that patients who extensively metabolize tamoxifen into endoxifen have superior outcomes relative to patients who do not, supporting a primary role for endoxifen in driving tamoxifen responses. Therefore, “tamoxifen resistance” may be better modeled by “endoxifen resistance” for some patients. Here, we report the development of novel endoxifen-resistant breast cancer cell lines and have extensively compared these models to 4HT and fulvestrant (ICI)-resistant models. Endoxifen-resistant cells were phenotypically and molecularly distinct from 4HT-resistant cells and more closely resembled ICI-resistant cells overall. Specifically, endoxifen resistance was associated with ERa and PR loss, estrogen insensitivity, unique gene signatures, and striking resistance to most FDA-approved second- and third-line therapies. Given these findings, and the importance of endoxifen in the efficacy of tamoxifen therapy, our data indicate that endoxifen-resistant models may be more clinically relevant than existing models and suggest that a better understanding of endoxifen resistance could substantially improve patient care. Implications: Here we report on the development and characterization of the first endoxifen-resistant models and demonstrate that endoxifen resistance may better model tamoxifen resistance in a subset of patients.
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U2 - 10.1158/1541-7786.MCR-20-0872
DO - 10.1158/1541-7786.MCR-20-0872
M3 - Article
C2 - 33627502
AN - SCOPUS:85107197402
SN - 1541-7786
VL - 19
SP - 1026
EP - 1039
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 6
ER -