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Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors
Hyunsoo Kim1, Austin A Whitman1, Kamila Wisniewska1
1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
Abstract:
In ER+/HER2- breast cancer, multiple measures of intra-tumor heterogeneity are associated with worse response to endocrine therapy. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live human tumors and normal breast specimens immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from 3 distinct resistant subpopulations are prognostic in large cohorts of ER+ breast cancer patients and enriched in endocrine therapy resistant tumors. This novel ex vivo model system now provides a foundation to define responsive and resistant sub-populations within heterogeneous tumors, to develop precise single cell-based predictors of response to therapy, and to identify genes and pathways driving resistance to therapy.
Insights
Intra-tumor heterogeneity in ER+/HER2- breast cancer impacts endocrine therapy response. This study identifies distinct tamoxifen-responsive and resistant cell subpopulations, offering new avenues for personalized breast cancer treatment strategies.
Area of Science:
- Oncology
- Genomics
- Cell Biology
Background:
- Intra-tumor heterogeneity is linked to poorer outcomes in ER+/HER2- breast cancer treated with endocrine therapy.
- Understanding cellular responses to treatment is crucial for improving therapeutic efficacy.
Approach:
- Developed an "operating room-to-laboratory" pipeline for immediate processing of live human breast tumors and normal tissues post-resection.
- Utilized single-cell workflows for experimentation and genomic analyses to investigate treatment response at the cellular level.
- Identified distinct subpopulations of cancer cells with varying sensitivity to tamoxifen.
Key Points:
- Demonstrated cell-type-specific differences in tamoxifen response within human breast tumors.
- Identified distinct responsive and resistant subpopulations within the malignant cell compartment.
- Tamoxifen resistance signatures from resistant subpopulations are prognostic in ER+ breast cancer patients and associated with endocrine therapy resistance.
Conclusions:
- The novel ex vivo model enables the characterization of responsive and resistant subpopulations in heterogeneous tumors.
- This approach can lead to the development of single-cell-based predictors of therapy response.
- Facilitates the identification of key genes and pathways involved in endocrine therapy resistance.
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