title: Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation.
abstract: Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure.
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Tesa M
authors.initials: TM
authors.lastname: Severson
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.|Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Agendia NV, Amsterdam, XH, The Netherlands.
authors.forename: Justine
authors.initials: J
authors.lastname: Peeters
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Annelot
authors.initials: A
authors.lastname: van Rossum
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Droog
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.|Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, GA, The Netherlands.
authors.forename: Rutger
authors.initials: R
authors.lastname: Koornstra
authors.affiliation: Agendia NV, Amsterdam, XH, The Netherlands.
authors.forename: Inès
authors.initials: I
authors.lastname: Beumer
authors.affiliation: Agendia NV, Amsterdam, XH, The Netherlands.
authors.forename: Annuska M
authors.initials: AM
authors.lastname: Glas
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peeper
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: Agendia NV, Amsterdam, XH, The Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.|Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.|Department of Pathology, University Medical Center Utrecht, CX, The Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D056915:DNA Copy Number Variations; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009426:Netherlands; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011485:Protein Binding; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013629:Tamoxifen / Q000008:administration & dosage*; D013997:Time Factors; D014158:Transcription, Genetic; D059467:Transcriptome / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen
keywords: ChIP-seq; endocrine therapy; estrogen receptor; gene expression analysis; neoadjuvant therapy