Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells

• Published in: Cell cycle (Georgetown, Tex.) Vol. 12; no. 22; pp. 3471 - 3477
• Main Authors: Vazquez-Martin, Alejandro, CUFÍ, SÍLVIA, López-Bonet, Eugeni, COROMINAS-FAJA, BRUNA, CUYÀS, ELISABET, Vellon, Luciano, MANUEL IGLESIAS, JUAN, LEIS, OLATZ, Martin, Angel, MENENDEZ MENENDEZ, JAVIERABEL
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 15.11.2013; Landes Bioscience
• Subjects: Animals; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cancer stem cells; Cell Line, Tumor; Cellular Reprogramming; estradiol; Estradiol - pharmacology; Estradiol - physiology; estrogen receptor; Estrogen Receptor alpha - metabolism; Estrogens - pharmacology; Estrogens - physiology; Extra Views; Female; Humans; MCF-7 Cells; Mice; Mice, Nude; Neoplastic Stem Cells - physiology; Phosphorylation; Receptors, Progesterone - metabolism; Signal Transduction; SOX2; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; SOX2; breast cancer; cancer stem cells; estrogen receptor; estradiol
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.26692

The restoration of pluripotency circuits by the reactivation of endogenous stemness factors, such as SOX2, may provide a new paradigm in cancer development. The tumoral stem cell reprogramming hypothesis, i.e., the ability of stemness factors to redirect normal and differentiated tumor cells toward a less-differentiated and stem-like state, adds new layers of complexity to cancer biology, because the effects of such reprogramming may remain dormant until engaged later in response to (epi)genetic and/or (micro)environmental events. To test this hypothesis, we utilized an in vitro model of a SOX2-overexpressing cancer stem cell (CSC)-like cellular state that was recently developed in our laboratory by employing Yamanaka's nuclear reprogramming technology in the estrogen receptor α (ERα)-positive MCF-7 breast cancer cell line. Despite the acquisition of distinct molecular features that were compatible with a breast CSC-like cellular state, such as strong aldehyde dehydrogenase activity, as detected by ALDEFLUOR, and overexpression of the SSEA-4 and CD44 breast CSC markers, the tumor growth-initiating ability of SOX2-overexpressing CSC-like MCF-7 cells solely occurred in female nude mice supplemented with estradiol when compared with MCF-7 parental cells. Ser118 phosphorylation of estrogen receptor α (ERα), which is a pivotal integrator of the genomic and nongenomic E 2 /ERα signaling pathways, drastically accumulated in nuclear speckles in the interphase nuclei of SOX2-driven CSC-like cell populations. Moreover, SOX2-positive CSC-like cells accumulated significantly higher numbers of actively dividing cells, and the highest levels of phospho-Ser118-ERα occurred when chromosomes lined up on a metaphase plate. The previously unrecognized link between E 2 /ERα signaling and SOX2-driven stem cell circuitry may significantly impact our current understanding of breast cancer initiation and progression, i.e., SOX2 can promote non-genomic E 2 signaling that leads to nuclear phospho-Ser118-ERα, which ultimately exacerbates genomic ER signaling in response to E 2 . Because E 2 stimulation has been recently shown to enhance breast tumor-initiating cell survival by downregulating miR-140, which targets SOX2, the establishment of a bidirectional cross-talk interaction between the stem cell self-renewal regulator, SOX2, and the local and systemic ability of E 2 to increase breast CSC activity may have profound implications for the development of new CSC-directed strategies for breast cancer prevention and therapy.