Development and Characterization of Novel Endoxifen-Resistant Breast Cancer Cell Lines Highlight Numerous Differences
Calley J Jones1, Malayannan Subramaniam1, Michael J Emch1
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Abstract:
Despite the availability of drugs that target ERα-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 ERα 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.
Insights
Endoxifen resistance, not tamoxifen resistance, may better predict treatment failure in some ERα-positive breast cancers. New models show endoxifen resistance is linked to distinct molecular changes and therapy resistance.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Tamoxifen is a widely used endocrine therapy for ERα-positive breast cancer, but resistance frequently develops, leading to poor patient outcomes.
- Endoxifen, a major active metabolite of tamoxifen, plays a crucial role in treatment efficacy, yet resistance to endoxifen itself is understudied.
- Existing models of tamoxifen resistance may not fully capture resistance mechanisms driven by endoxifen.
Purpose of the Study:
- To develop and characterize novel endoxifen-resistant breast cancer cell lines.
- To compare endoxifen-resistant models with 4-hydroxy-tamoxifen (4HT) and fulvestrant (ICI)-resistant models.
- To investigate the clinical relevance of endoxifen resistance in breast cancer treatment.
Main Methods:
- Development of endoxifen-resistant breast cancer cell lines.
- Phenotypic and molecular characterization of resistant cell lines.
- Comparison of endoxifen-resistant cells with 4HT- and ICI-resistant cells.
Main Results:
- Endoxifen-resistant cells exhibited distinct phenotypes and molecular profiles compared to 4HT-resistant cells.
- Endoxifen resistance was associated with loss of ERα and PR, estrogen insensitivity, and unique gene signatures.
- Endoxifen-resistant models showed significant resistance to multiple FDA-approved therapies, resembling ICI-resistant models more closely.
- Endoxifen-resistant cells were distinct from 4HT-resistant cells.
Conclusions:
- Endoxifen resistance may be a more clinically relevant model for tamoxifen resistance in certain patient populations.
- Understanding endoxifen resistance mechanisms is crucial for improving therapeutic strategies in breast cancer.
- Novel endoxifen-resistant models provide valuable tools for studying resistance and developing new treatments.
