Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors

Abstract Purpose: In estrogen receptor–positive (ER+)/HER2− breast cancer, multiple measures of intratumor heterogeneity are associated with a worse response to endocrine therapy. We sought to develop a novel experimental model to measure heterogeneity in response to tamoxifen treatment in primary breast tumors. Experimental Design: To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live normal breast specimens and human tumors immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. Live primary cell suspensions were treated ex vivo with tamoxifen (10 µmol/L) or control media for 12 hours, and single-cell RNA libraries were generated using the 10X Genomics droplet-based kit. Results: In total, we obtained and processed normal breast tissue from two women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2− invasive breast carcinoma. 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 resistant subpopulations predict poor outcomes in two large cohorts of ER+ breast cancer patients and are enriched in endocrine therapy–resistant tumors. Conclusions: This novel ex vivo model system now provides the foundation to define responsive and resistant subpopulations within heterogeneous human tumors, which can be used to develop precise single cell–based predictors of response to therapy and to identify genes and pathways driving therapeutic resistance.

• Publication year

  2023

• Venue

  Clinical Cancer Research

• Publication date

  2023-09-25

• Fields of study

  Medicine

• Identifiers
  DOI 10.1158/1078-0432.CCR-23-1248PMID 37747807PMCID 10690085
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2021influential reference
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  2020cited by this paper
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  2020influential reference
• Cancer statistics, 2019

  2019cited by this paper
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  2019cited by this paper
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  2019cited by this paper
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  2019cited by this paper
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  2018cited by this paper
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  2018cited by this paper
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  2018cited by this paper
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  2016influential reference
• The origin of breast tumor heterogeneity

  2015cited by this paper
• Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity

  2015cited by this paper
• The Molecular Signatures Database (MSigDB) hallmark gene set collection.

  2015cited by this paper
• The Sweden Cancerome Analysis Network - Breast (SCAN-B) Initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine

  2015cited by this paper
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  2014cited by this paper
• R: A language and environment for statistical computing.

  2014influential reference
• Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.

  2013cited by this paper
• Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.

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  2012influential reference
• The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

  2012cited by this paper
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  2012cited by this paper
• Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes

  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2010cited by this paper
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  2010cited by this paper
• Supervised risk predictor of breast cancer based on intrinsic subtypes.

  2009cited by this paper
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  2009cited by this paper
• Biological determinants of endocrine resistance in breast cancer

  2009cited by this paper
• Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics

  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
• Predicting response and resistance to endocrine therapy

  2008cited by this paper
• Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures

  2008cited by this paper
• Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers.

  2006cited by this paper
• Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen.

  2006cited by this paper
• Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.

  2005cited by this paper
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  2005cited by this paper
• Mutation of GATA3 in human breast tumors

  2004cited by this paper
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  2004cited by this paper
• Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

  2003cited by this paper
• Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

  2003cited by this paper
• Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

  2003cited by this paper
• Molecular portraits of human breast tumours

  2000cited by this paper
• Cellularity of Lobular Carcinoma and Its Relationship to False Negative Fine Needle Aspiration Results

  2000cited by this paper
• Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

  1999cited by this paper
• Tumor heterogeneity and the biology of cancer invasion and metastasis.

  1978cited by this paper

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  2025cites this paper
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