title: Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.
abstract: Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies.
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece; Institute of Applied Computational Mathematics, Foundation of Research and Technology (FORTH), Heraklion, Greece. Electronic address: gnotas@med.uoc.gr.
authors.forename: George
authors.initials: G
authors.lastname: Notas
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece; Laboratories of Pathology, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Pelekanou
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Kampa
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Alexakis
authors.affiliation: Institute of Computer Science, Foundation of Research and Technology (FORTH), Heraklion, Greece.
authors.forename: Stelios
authors.initials: S
authors.lastname: Sfakianakis
authors.affiliation: Department of Surgical Oncology, University Hospital, Heraklion, Greece.
authors.forename: Aggelos
authors.initials: A
authors.lastname: Laliotis
authors.affiliation: Department of Surgical Oncology, University Hospital, Heraklion, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Askoxilakis
authors.affiliation: Laboratories of Pathology, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsentelierou
authors.affiliation: Laboratories of Pathology, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Tzardi
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece; INSERM U976, Hôpital Saint Louis, Paris, France; University Paris Diderot, Paris, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tsapis
authors.affiliation: Laboratories of Experimental Endocrinology, University of Crete School of Medicine, Heraklion, Greece. Electronic address: castanas@med.uoc.gr.
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D050697:Retinal Dehydrogenase; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: Breast cancer; Cell lines; Endocrine resistance; Patient data; Pluripotency; Tamoxifen; Transcriptomic analysis