Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors

• Published in: Molecular oncology 2015-11, Vol.9 (9), p.1744-1759
• Main Authors: Notas, George, Pelekanou, Vassiliki, Kampa, Marilena, Alexakis, Konstantinos, Sfakianakis, Stelios, Laliotis, Aggelos, Askoxilakis, John, Tsentelierou, Eleftheria, Tzardi, Maria, Tsapis, Andreas, Castanas, Elias
• Format: Article
• Language: English
• Subjects: Aldehyde Dehydrogenase - analysis; Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase 1 Family; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Apoptosis; Breast - drug effects; Breast - metabolism; Breast - pathology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell cycle; Cell Line, Tumor; Cell lines; Cloning; Collaboration; Drug resistance; Drug Resistance, Neoplasm; Endocrine resistance; Endocrine therapy; Enzymes; Estrogen Receptor alpha - analysis; Estrogen receptors; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Localization; Medical prognosis; Menopause; Metabolism; Metastasis; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Patient data; Patients; Phenotypes; Pluripotency; Retinal Dehydrogenase; Stem cells; Surgery; Tamoxifen; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Transcription; Transcriptome - drug effects; Transcriptomic analysis; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor cell lines; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.05.008

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. •Tamoxifen transcriptomics of breast cancer cells reveal ERα-dependent genes related to pluripotency.•Tamoxifen-treated ERα-positive breast cancer