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

Content Provider	Scilit
Author	Vázquez-Martín, Alejandro Cufí, Sílvia López-Bonet, Eugeni Corominas-Faja, Bruna Cuyàs, Elisabet Vellon, Luciano Iglesias, Juan Manuel Leis, Olatz Martin, Angel Garcia Menendez, Javier A.
Copyright Year	2013
Abstract	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 E2/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 E2/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 E2 signaling that leads to nuclear phospho-Ser118-ERα, which ultimately exacerbates genomic ER signaling in response to E2. Because E2 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 E2 to increase breast CSC activity may have profound implications for the development of new CSC-directed strategies for breast cancer prevention and therapy.
Related Links	http://www.tandfonline.com/doi/pdf/10.4161/cc.26692?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906332/pdf
Ending Page	3477
Page Count	7
Starting Page	3471
ISSN	15384101
e-ISSN	15514005
DOI	10.4161/cc.26692
Journal	Cell Cycle
Issue Number	22
Volume Number	12
Language	English
Publisher	Informa UK Limited
Publisher Date	2013-11-15
Access Restriction	Open
Subject Keyword	Journal: Cell Cycle Biochemistry and Molecular Biology Sox2 Breast Cancer Cancer Stem Cells Estradiol Estrogen Receptor
Content Type	Text
Resource Type	Article
Subject	Cell Biology Developmental Biology Medicine Molecular Biology