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.

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

“…The major actions of chalcone derivatives in cancer include inducing apoptosis, regulating cell proliferation, scavenging reactive oxygen species (ROS), and inhibiting tumor invasion and metastasis . Our earlier studies also reported that the sulfonamide chalcones were effective apoptotic agent against the human lymphatic filarial parasite Brugia malayi .…”

“…Interestingly, estrogen receptor (ER)‐independent mechanisms of tamoxifen in these TNBCs were observed, as reported earlier by Notas et al . : an induction of pluripotency factors (ALDH1A3, Sox2 and Oct1), autophagy, mitochondrial, transporters, microtubules and catabolism‐related protein expression in MDA‐MB‐231 treated with tamoxifen. This led us to evaluate the apoptotic effect of sulfonamide chalcones and their thia‐Michael adducts , as synthesized and reported previously, against these TNBCs as well as to perform molecular docking with GSTO1.…”

miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

“…Breast cancer is a heterogeneous disease which is classified into several major subtypes according to the expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu) (2). Targeted therapies, such as tamoxifen and trastuzumab, have improved the outcomes of patients with ER + or HER2 + breast cancer (3,4). However, a number of patients with breast cancer exhibit de novo or acquired target therapy resistance (5,6).…”

BCMA (TNFRSF17) Induces APRIL and BAFF Mediated Breast Cancer Cell Stemness

“…However, another element of this heterogeneity has been recently identified and is related to the effects of administered treatment to the transformation of cancer epithelial cells ( 44 ), including the emergence of cell pluripotency. Recently, we have reported that short term exposure of breast cancer cells to tamoxifen may act as such an epigenetic stem-inducing stimulus ( 45 ). In the present work we provide evidence that an increase in breast cancer stem population can be induced by the two TNF superfamily cytokines BAFF and APRIL through a BCMA-JNK pathway.…”