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Peer-reviewedCC BYBreast Cancer: Targets and Therapy

BCAR4, BCAR3 and EGFR Display Different Degrees of Cross-Resistance to Endocrine Mono- and Combination Therapies in Hormone Receptor Positive, HER2 Negative Breast Cancer

  • Huang Z1
  • Wortelboer N1
  • Beaufort CM1
  • Ortak SN
  • Chan DW2
  • Helmijr J3
  • Jager A
  • Martens JWM1
  • Jansen MPHM
  1. 1Medical Oncology
  2. 2Internal Oncology
  3. 3Medical oncology
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Abstract

Zhangzan Huang, Noor Wortelboer, Corine M Beaufort, Seda Nur Ortak, Da-wei Chan, Jean Helmijr, Agnes Jager, John WM Martens, Maurice PHM JansenDepartment of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands&ast;These authors contributed equally to this workCorrespondence: Maurice PHM Jansen, Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, Rotterdam, CA, 3000, Netherlands, Email [email protected]: Failure of multiple treatment lines in hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer patients may result in cross-resistance. This study aimed to determine if previously identified cell lines carried on tamoxifen-resistant genes can cause cross-resistance to other commonly used (combination) endocrine treatments in HR+/HER2- breast cancer.Materials and Methods: MCF7 parental cells were compared with tamoxifen-resistant models of transformed cells overexpressing BCAR3, BCAR4 or EGFR. Dose–response experiments were conducted with tamoxifen, fulvestrant, three CDK4/6-inhibitors and alpelisib for 10 days, as both monotherapies and combinations. ZR75.1 parental and BCAR4 cell lines were used as validation. Lapatinib was tested to reverse the phenotype induced by BCAR4. Half maximal inhibitory concentration (IC50) was determined and resistance was defined as higher IC50 in transformed cells compared to parental cells (p< 0.05, Mann–Whitney U-test). The IC50 p-values were adjusted for multiple testing using Holm–Bonferroni correction. All experiments were performed with at least four independent replicates.Results: MCF7 BCAR4 exhibited cross-resistance (p< 0.05) to endocrine therapy, CDK4/6 and PIK3CA inhibitors, as well as trends of cross-resistance (p< 0.1) in their combinations. This broad cross-resistance induced by BCAR4 could be entirely reversed by lapatinib treatment. However, the ZR75.1 BCAR4 model did not replicate cross-resistance, suggesting that the BCAR4 induced cross-resistance may be a cell line context-dependent finding. MCF7 BCAR3 and EGFR showed resistance to tested endocrine therapies and different responses to combination therapies.Conclusion: The tamoxifen-resistant genes BCAR3, BCAR4 and EGFR showed various degrees of (cross-)resistance to current breast cancer treatments. Notably, BCAR4 overexpression in MCF7 cells, but not in ZR75.1 cells, was associated with reduced response to clinically used combination treatments, underscoring the context-dependent effects of BCAR4 as a key finding of this study. This suggests a potential need for biomarker-guided patient stratification in specific tumor contexts. Importantly, this resistance may be therapeutically actionable, as the addition of the HER2 inhibitor lapatinib appeared to mitigate the resistant phenotype.Keywords: breast cancer, endocrine therapy, CDK4/6-inhibitor, PI3 kinase inhibitor, cross-resistance

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Cite

BibTeXRIS
BibTeX
@article{huang2026bcar4,
  title = {{BCAR4, BCAR3 and EGFR Display Different Degrees of Cross-Resistance to Endocrine Mono- and Combination Therapies in Hormone Receptor Positive, HER2 Negative Breast Cancer}},
  author = {Huang Z and Wortelboer N and Beaufort CM and Ortak SN and Chan DW and Helmijr J and Jager A and Martens JWM and Jansen MPHM},
  journal = {Breast Cancer: Targets and Therapy},
  year = {2026},
  month = nov,
  url = {https://www.dovepress.com/bcar4-bcar3-and-egfr-display-different-degrees-of-cross-resistance-to--peer-reviewed-fulltext-article-BCTT},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - BCAR4, BCAR3 and EGFR Display Different Degrees of Cross-Resistance to Endocrine Mono- and Combination Therapies in Hormone Receptor Positive, HER2 Negative Breast Cancer
AU  - Huang Z
AU  - Wortelboer N
AU  - Beaufort CM
AU  - Ortak SN
AU  - Chan DW
AU  - Helmijr J
AU  - Jager A
AU  - Martens JWM
AU  - Jansen MPHM
PY  - 2026
DA  - 2026/11/08
JO  - Breast Cancer: Targets and Therapy
UR  - https://www.dovepress.com/bcar4-bcar3-and-egfr-display-different-degrees-of-cross-resistance-to--peer-reviewed-fulltext-article-BCTT
AB  - Zhangzan Huang, Noor Wortelboer, Corine M Beaufort, Seda Nur Ortak, Da-wei Chan, Jean Helmijr, Agnes Jager, John WM Martens, Maurice PHM JansenDepartment of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands&ast;These authors contributed equally to this workCorrespondence: Maurice PHM Jansen, Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, Rotterdam, CA, 3000, Netherlands, Email [email protected]: Failure of multiple treatment lines in hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer patients may result in cross-resistance. This study aimed to determine if previously identified cell lines carried on tamoxifen-resistant genes can cause cross-resistance to other commonly used (combination) endocrine treatments in HR+/HER2- breast cancer.Materials and Methods: MCF7 parental cells were compared with tamoxifen-resistant models of transformed cells overexpressing BCAR3, BCAR4 or EGFR. Dose–response experiments were conducted with tamoxifen, fulvestrant, three CDK4/6-inhibitors and alpelisib for 10 days, as both monotherapies and combinations. ZR75.1 parental and BCAR4 cell lines were used as validation. Lapatinib was tested to reverse the phenotype induced by BCAR4. Half maximal inhibitory concentration (IC50) was determined and resistance was defined as higher IC50 in transformed cells compared to parental cells (p< 0.05, Mann–Whitney U-test). The IC50 p-values were adjusted for multiple testing using Holm–Bonferroni correction. All experiments were performed with at least four independent replicates.Results: MCF7 BCAR4 exhibited cross-resistance (p< 0.05) to endocrine therapy, CDK4/6 and PIK3CA inhibitors, as well as trends of cross-resistance (p< 0.1) in their combinations. This broad cross-resistance induced by BCAR4 could be entirely reversed by lapatinib treatment. However, the ZR75.1 BCAR4 model did not replicate cross-resistance, suggesting that the BCAR4 induced cross-resistance may be a cell line context-dependent finding. MCF7 BCAR3 and EGFR showed resistance to tested endocrine therapies and different responses to combination therapies.Conclusion: The tamoxifen-resistant genes BCAR3, BCAR4 and EGFR showed various degrees of (cross-)resistance to current breast cancer treatments. Notably, BCAR4 overexpression in MCF7 cells, but not in ZR75.1 cells, was associated with reduced response to clinically used combination treatments, underscoring the context-dependent effects of BCAR4 as a key finding of this study. This suggests a potential need for biomarker-guided patient stratification in specific tumor contexts. Importantly, this resistance may be therapeutically actionable, as the addition of the HER2 inhibitor lapatinib appeared to mitigate the resistant phenotype.Keywords: breast cancer, endocrine therapy, CDK4/6-inhibitor, PI3 kinase inhibitor, cross-resistance
SN  - 1179-1314
ER  -