Expression of embryonal stem cell transcription factors in breast cancer: Oct4 as an indicator for poor clinical outcome and tamoxifen resistance

Abstract

The transcription factors of embryonic stem cells, such as Oct4, Sox2, Nanog, Bmi1, and Klf4, are known to be associated with stemness, epithelial–mesenchymal transition and aggressive tumor behavior. This study was designed to evaluate the clinicopathological significance of their expression in breast cancer. Immunohistochemistry for Oct4, Sox2, Nanog, Bmi1, and Klf4 was performed in 319 cases of invasive breast cancer. The relationship between the expression of these markers and clinicopathologic features of the tumors, including breast cancer stem cell phenotype and epithelial–mesenchymal transition marker expression, and their prognostic value in breast cancer, were analyzed. Expression of Oct4 and Sox2 was commonly associated with high histologic grade and high Ki-67 index in the whole group and in the hormone receptor-positive subgroup. On the other hand, expression of Nanog, Bmi1, and Klf4 was inversely correlated with aggressive features of the breast cancer. Oct4 expression was associated with ALDH1 expression but not with epithelial–mesenchymal transition marker expression. In survival analysis, Oct4 expression was independently associated with poor prognosis in the whole group and in the hormone receptor-positive subgroup, but not in hormone receptor-negative subgroup. Particularly, Oct4 expression was associated with poor clinical outcome in patients with hormone receptor-positive breast cancer treated with tamoxifen. Our results indicate that Oct4 expression is associated with aggressive features, ALDH1 expression, tamoxifen resistance and poor clinical outcomes in hormone receptor-positive breast cancer, and thus may be useful as a predictive and prognostic marker in this subgroup of breast cancer.

Targeting cancer stem cell pathways for cancer therapy

“…78 Data also show that Oct4 expression is associated with poor clinical outcome in hormone receptor-positive breast cancer. 79 Knockdown of Oct4 also reduces the stemness of germ cell tumors. 80 Hence, these studies have proven that Oct4 is a pluripotent factor in CSCs.…”

KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

“…Increased stability of the KLF4 protein, which is mediated by the ubiquitin-proteasomal pathway, is linked to an oncogenic role in breast cancer (Hu et al 2012), and decreased stability is linked to its tumor suppressor role in colorectal cancer (Gamper et al 2012). KLF4 stability modulation by interaction with the pluripotency transcription factors may also be important in tumorigenesis, as coexpression of these factors is associated with a variety of cancers such as breast cancer, squamous cell carcinoma, and gastrointestinal cancer progression (Hu et al 2012;Lu et al 2014;Piva et al 2014;Almozyan et al 2017;Gwak et al 2017;Soheili et al 2017).…”

SOX8 regulates cancer stem‐like properties and cisplatin‐induced EMT in tongue squamous cell carcinoma by acting on the Wnt/β‐catenin pathway

“…Tumor cells with a more aggressive phenotype display strong self‐renewal capacity and tumorigenicity under average chemotherapy pressure, which are similar characteristics to those harboured by CSCs that enable them to escape drug‐induced cell death . For example, Oct4 overexpression contributes to tamoxifen resistance and ALDH1 upregulation in hormone receptor‐positive breast cancer . Silencing SOX2 expression also attenuates the resistance to cisplatin in glioblastoma multiforme .…”

“…39,40 For example, Oct4 overexpression contributes to tamoxifen resistance and ALDH1 upregulation in hormone receptor-positive breast cancer. 41 Silencing SOX2 expression also attenuates the resistance to cisplatin in glioblastoma multiforme. 42 Our study demonstrated that chemoresistant TSCC cells acquired abilities similar to CSCs, which were accompanied by an increase in the CSC markers ABCG2, SOX2, OCT4, and BMI1 as well as strong self-renewal capacity and tumorigenicity in vivo.…”