Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Abstract

We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

The Clinical and Molecular Characteristics of Sex-Determining Region Y-Box 2 and its Prognostic Value in Breast Cancer: A Systematic Meta-Analysis

“…Our pooled data suggested that SOX2 expression was not correlated with ER status, PR status, and TN status of breast cancer, which were consistent with the previous studies regarding the correlation between SOX2 expression and ER status [23, 24, 26, 31, 34, 36, 38], PR status [23, 24, 26, 31, 36, 39], and TN status [24, 26, 31, 34, 36, 38]. Some studies reported that SOX2 expression was related to HER2 status [26] and EGFR status [30].…”

“…No significant relationship was observed between SOX2 expression and lymph node metastasis and lymphovascular invasion of patients with breast cancer, which was consistent with the previous publications regarding SOX2 expression with lymph node metastasis [20, 23, 24, 31, 36, 37, 38, 41] and lymphovascular invasion [20, 24, 31, 36]. Some previous publications reported that SOX2 expression was positively linked to tumor grade [5, 20, 21, 23, 24, 32, 33, 36, 38, 39, 41], clinical stage [22, 32, 38], and pT stage [20, 23, 30], which were consistent with our results that showed that SOX2 expression was associated with advanced tumor grade, clinical stage, and pT stage. This suggests that SOX2 expression plays an important role in the progression of breast cancer.…”

“…When these 3 studies [22, 26, 32] were deleted, the re-calculated result was still not associated with lymph node metastasis ( p = 0.186), with no heterogeneity ( p = 0.141). When the study of Gupta et al [39] (2018) was deleted, the re-calculated result was still not correlated with lymphovascular invasion ( p = 0.085), with no evidence of heterogeneity ( p = 0.634).…”

“…When 3 studies [33, 37, 39] were removed, the re-calculated result was significantly changed, showing a negative association with ER status (OR = 0.62, p = 0.001) and no evidence of heterogeneity ( p = 0.384). When the study of Abd El-Maqsoud et al [33] (2014) was removed, the re-calculated result was still not correlated with PR status ( p = 0.305), with no heterogeneity ( p = 0.112).…”

“…We analyzed whether SOX2 expression was correlated with the clinical and molecular features of patients with breast cancer. SOX2 expression was not associated with age factor [20, 22, 23, 26, 33, 35, 37-39, 41] and menopausal status [22, 30, 33, 34, 36] among all studies. Our pooled results remained consistent, showing no correlation between SOX2 expression and age and menopausal status.…”