The Regulation of SOX7 and Its Tumor Suppressive Role in Breast Cancer

Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
American Journal Of Pathology (Impact Factor: 4.59). 09/2013; 346(5). DOI: 10.1016/j.ajpath.2013.07.025
Source: PubMed


Both epigenetic silencing and genetic deletion of tumor suppressors contribute to the development and progression of breast cancer. SOX7 is a transcription factor important to development, and its down-regulation has been reported in tumor tissues and cell lines of prostate, colon, and lung cancers. However, the regulation of SOX7 expression and its functional role in breast cancer have not been reported. The current study demonstrates that SOX7 mRNA and protein expression are down-regulated in breast cancer tissues and cell lines compared with adjacent normal tissues and nontumorigenic cells, respectively. The SOX7 promoter is hypermethylated in breast cancer cell lines compared with nontumorigenic cells, and the inhibition of DNA methylation increases SOX7 mRNA levels. With shRNA-mediated SOX7 silencing, nontumorigenic immortal breast cells display increased proliferation, migration, and invasion and form structures that resemble that of breast cancer cells in a three-dimensional culture system. Conversely, ectopic SOX7 expression inhibits proliferation, migration, and invasion of breast cancer cells in vitro and tumor growth in vivo. Importantly, we discovered that SOX7 transcript levels positively correlated with clinical outcome of 674 breast cancer patients. Overall, data suggest that SOX7 acts as a tumor suppressor in breast cancer. SOX7 expression is likely regulated by multiple mechanisms and potentially serves as a prognostic marker for breast cancer patients.

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    • "Recently, SOX7 is proposed to function in tumorigenesis depending on the tumor type. For example, SOX7 is up-regulated in pancreatic cancer cell lines and primary gastric cancer cases [12], but down-regulated in primary colorectal tumors, prostate cancer, lung cancer and breast cancer [13]–[16]. However, its role in HCC remains unclear. "
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    ABSTRACT: SOX7 is a transcription factor mediating various developmental processes. However, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we assessed the role of SOX7 in hepatocarcinogenesis. We found HCC samples exhibited lower levels of SOX7 mRNA and protein expression than non-tumor samples, and the expression of SOX7 was negatively correlated with tumor size. SOX7 expression was also reduced in four HCC cell lines (SMMC-7721, Hep3B, HepG2 and Huh 7). Overexpression of SOX7 could inhibit HCC cell growth, with G1to S phase arrest. In SOX7-overexpression cells, cyclin D1 and c-myc, two cell cycle promoters, were down-regulated. Moreover, ectopic expression of cyclin D1 or c-myc could override G1 to S pahse arrest induced by SOX7. Furthermore, overexpression of SOX7 suppressed tumor formation with down-regulation of cyclin D1 and c-myc in vivo. The expression of Ki-67, a proliferation marker, was also reduced in SOX7-overexpression tumors. Taken together, our study suggests that SOX7 plays an important inhibitory role in hepatocarcinogenesis, and might be a novel target for HCC therapy.
    PLoS ONE 05/2014; 9(5):e97433. DOI:10.1371/journal.pone.0097433 · 3.23 Impact Factor
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    ABSTRACT: SOX7 belongs to the SOX (SRY-related HMG-box) family of transcription factors that have been shown to regulate multiple biological processes, such as hematopoiesis, vasculogenesis and cardiogenesis during embryonic development. Recent studies indicate that several SOX family members play important roles in tumorigenesis. In this review, we introduce SOX7 gene and protein structures, and discuss its expression and functional role in cancer development and progression. SOX7 is frequently downregulated in many human cancers and its reduced expression correlates with poor prognoses of several cancers. Functional studies reveal many tumor suppressive properties of SOX7 in prostate, colon, lung, and breast cancers. To date, although a few target genes of SOX7 have been identified, SOX7-mediated gene expression has not been investigated in a cancer-relevant context. Our recent studies not only for the first time demonstrate a tumor suppressive role of SOX7 in a xenograft mouse model, but also unravel that many genes regulating cell death, growth and apoptosis are affected by SOX7, strongly supporting a pivotal role of SOX7 in tumorigenesis. Thus, currently available data clearly indicate a tumor suppressive role of SOX7, but the mechanisms underlying its gene expression and tumor suppressive activity remain undetermined. The research of SOX7 in cancers remains a fertile area to be explored.
    Histology and histopathology 11/2013; 29(4). · 2.10 Impact Factor
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    ABSTRACT: SOX genes are transcription factors with important roles in embryonic development and carcinogenesis. The SOX family of 20 genes is responsible for regulating lineage and tissue specific gene expression patterns, controlling numerous developmental processes including cell differentiation, sex determination, and organogenesis. As is the case with many genes involved in regulating development, SOX genes are frequently deregulated in cancer. In this perspective we provide a brief overview of how SOX proteins can promote or suppress cancer growth. We also present a pan-cancer analysis of aberrant SOX gene expression and highlight potential molecular mechanisms responsible for their disruption in cancer. Our analyses indicate the prominence of SOX deregulation in different cancer types and reveal potential roles for SOX genes not previously described in cancer. Finally, we summarize our recent identification of SOX15 as a candidate tumor suppressor in pancreatic cancer and propose several research avenues to pursue to further delineate the emerging role of SOX15 in development and carcinogenesis.
    06/2014; 1(5):326-35. DOI:10.18632/oncoscience.46
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