The Molecular Mechanism Governing the Oncogenic Potential of SOX2 in Breast Cancer

Abstract

SOX genes encode a family of high-mobility group transcription factors that play critical roles in organogenesis. The functional specificity of different SOX proteins and the tissue specificity of a particular SOX factor are largely determined by the differential partnership of SOX transcription factors with other transcription regulators, many of which have not yet been discovered. Virtually all members of the SOX family have been found to be deregulated in a wide variety of tumors. However, little is known about the cellular and molecular behaviors involved in the oncogenic potential of SOX proteins. Using cell culture experiments, tissue analysis, molecular profiling, and animal studies, we report here that SOX2 promotes cell proliferation and tumorigenesis by facilitating the G 1 /S transition and through its transcription regulation of the CCND1 gene in breast cancer cells. In addition, we identified ␤-catenin as the transcription partner for SOX2 and demonstrated that SOX2 and ␤-catenin act in synergy in the transcription regulation of CCND1 in breast cancer cells. Our experiments not only determined a role for SOX2 in mammary tumorigenesis but also revealed another activity of the multifunctional protein, ␤-catenin.The SOX 2 gene family encodes a group of transcription factors that are characterized by a highly conserved high-mobility group (HMG) domain (1-3). These genes are found throughout the animal kingdom, are expressed in a restricted spatial-temporal pattern, and play critical roles in stem cell biology, organogenesis, and animal development (3, 4). For example, overexpression of Sox2 in mouse neural stem cells blocks their differentiation, and inhibition of Sox2 in these cells causes their premature exit from the cell cycle and differentiation into neurons(5). Depletion of Sox2 by RNA interference blocks the proliferation of neural stem-like cells and causes them to differentiate into neurons(6).Recently, a number of links have been found between SOX transcription factors and human cancers (7). For instance, SOX2 has been found to be an immunogenic antigen in 41% of small cell lung cancer patients (8) and in 29% of meningioma patients (9). Immunohistochemistry results suggest that SOX2 is involved in later events of carcinogenesis, such as invasion and metastasis of pancreatic intraepithelial neoplasia (10). SOX2 may also be involved in gastric carcinogenesis (11) and may be amplified in prostate cancers (12). Furthermore, SOX2 expression has been observed in 43% of basal cell-like breast carcinomas and was found to be strongly correlated with CK5/6, EGFR, and vimentin immunoreactivity, suggesting that SOX2 may play a role in conferring a less differentiated phenotype in these tumors (13).How SOX2 exerts its oncogenic potential is currently unknown. SOX proteins including SOX2 bind to specific DNA sequences (C(T/A)TTG(T/A)(T/A)) by means of their HMG domains in functioning as transcription factors to activate or repress target gene expression (2, 3). It is currently accepted that SOX proteins the...

Sox2 expression in breast tumours and activation in breast cancer stem cells

“…To investigate this issue we examined the presence of stem-like cells by assessing the expression of the major stem cell pluripotency regulators, Oct4, Sox2 and Nanog (Jaenisch and Young, 2008), in human natural breast tumours. We observed that Sox2 is expressed at the protein level in breast tumours, as expected (RodriguezPinilla et al, 2007;Chen et al, 2008). However, Sox2 expression was more prevalent in the early stages of tumour development and in the ductal areas of tumours that still showed intact ductal structures, as is the case of lung cancer (Sholl et al, 2010).…”

SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity

“…27 Chen et al 28 These observations indicate that SOX2 has a role in tumorigenicity of both gliomas and lung adenocarcinomas in vivo; however, its exact molecular mechanisms are still elusive.…”

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

“…[1][2][3][4] In this regard, SOX2, a member of the SRYrelated HMG-box family of transcription factors, has mainly been studied in embryonic stem cells and in reprogramming of adult somatic cells to a pluripotent stem cell state, and it has been recently recognized to promote aberrant stem cell selfrenewal signaling in breast cancer. [5][6][7] First, normal breast tissues express low levels of SOX2, but SOX2 in early-stage breast carcinomas is differentially reactivated in the ductal areas of tumors that still show intact ductal structures, which strongly suggests that SOX2 may be expressed during the initial phases of tumorigenesis. However, SOX2 is lost as the tumor progresses toward advanced stages.…”