Int J Clin Exp Med 2015;8(12):22382-22392www.ijcem.com /ISSN:1940-5901/IJCEM0015998

Original ArticleClinicopathological significance of Sox2 expression in patients with breast cancer: a meta-analysis

Yan Zheng1*, Biyong Qin2*, Fang Li3, Shengzhen Xu4, Shanshan Wang1, Li Li1

Departments of 1Nursing, 2Neurology, 3Oncology, 4Gynaecology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China. *Equal contributors.

Received September 11, 2015; Accepted December 8, 2015; Epub December 15, 2015; Published December 30, 2015

Abstract: Sex-determining region Y-box protein 2 (Sox2), an embryonic transcription factor located at chromosome 3q26.33, has been frequently demonstrated to be an important prognostic marker for various tumors, including breast cancer. However, its clinicopathological role in breast cancer has not been fully elucidated. To derive a more precise evaluation, we here performed a meta-analysis focusing on the association between Sox2 expression and various clinicopathological characteristics of breast cancer. Relevant publications were identified and retrieved us-ing PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Chinese Biomedical databases. Ten studies with a total of 1713 patients with breast cancer were included in our meta-analysis. Reported odds ratios (OR) and the corresponding 95% confidence intervals (95% CI) were pooled to assess the strengths of the analyzed associations. Our results revealed significant positive associations between Sox2 ex-pression and increased tumor size (pooled OR=2.61, 95% CI=1.91-3.58), histological grade (pooled OR=2.28, 95% CI=1.72-3.03), lymph node metastasis (pooled OR=4.17, 95% CI=1.20-14.45), and the highly aggressive triple-negative phenotype (pooled OR=2.64, 95% CI=1.11-6.29). However, no associations were observed for TNM stage and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 statuses. Overall, the results of this meta-analysis indicate that Sox2 may be considered as a prognostic marker for breast cancer. More well-designed studies with larger sample sizes are warranted to clarify the prognostic significance of Sox2 in breast cancer.

Keywords: Sox2, breast cancer, prognosis, meta-analysis

Introduction

Despite great advances in the prognostic meth-ods and treatments, breast cancer remains the most common malignancy in women, indicating a major public health challenge [1]. In recent years, the cancer stem cell (CSC) hypothesis has shed lights on the development of breast cancer, proposing that a pool of malignant cells with stem/progenitor cell properties and an enhanced capacity to progress compared to their more differentiated non-tumorigenic coun-terparts exists, and may be responsible for the poor clinical outcomes associated with breast cancer [2]. Recently, pluripotency roots of can-cer stem cells have been found to correlate to the embryonic signature in breast cancers, sug-gesting a vital role for embryonic stem cell-like cancer cells in tumor invasion, metastasis, and/or recurrence [3-5]. Hence, identification

of these cells through associated biomarkers may be a reasonable approach to improve the pathological diagnosis or for predicting the clini-cal outcome of breast cancer.

Sox2, a High Mobility Group (HMG) domain tran-scription factor located at chromosome 3q26.33 is reported to be involved in the regu-lation of self-renewal and pluripotency in embry-onic stem cells [6]. For instance, Sox2 has been found to be overexpressed in mouse neural stem cells, resulting in repression of differentia-tion, whereas inhibition of Sox2 conversely has been demonstrated to lead to premature exit from the cell cycle and differentiation into neu-rons [7]. Recently, a growing body of evidence has revealed the contribution of Sox2 to tumori-genesis, as well as suggested a number of links between Sox2 and the clinical progression of various types of tumors, including human

Sox2 expression and breast cancer

22383 Int J Clin Exp Med 2015;8(12):22382-22392

breast [8], pancreatic [9], and lung cancers [10]. Although the association between Sox2 expression and breast cancer patients has been extensively reported in the last 3 or 4 years, the results of these studies are not always in agreement. For example, Huang et al. [11] found that Sox2 was expressed more fre-quently in tumors of larger size and higher his-tological grade, whereas Piva et al. [12] failed to show an association between Sox2 expres-sion and tumor size. Moreover, in a study by Rodriguez et al. [8], no significant differences in Sox2 expression between breast cancer patients with different histological grades were observed. These inconsistent results may be due to insufficient numbers of samples, as well as other factors. Accordingly, we here carried out a meta-analysis of relevant studies pub-lished on the topic to quantitatively evaluate the clinicopathological significance of Sox2 in breast cancer.

Materials and methods

Search strategy

Relevant papers included in this meta-analysis were systematically searched in the PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Chinese Biomedical databases (up until April 2014), using the following limits: Human, article in English or Chinese. Combinations of the following search string were used to screen for potentially related studies: (“Sox2” OR “sex-determining region Y-box protein 2”) AND (“breast cancer” OR “breast carcinoma”). The reference lists of major textbooks, review arti-cles, and all of the articles identified by the search were then individually and manually searched to find other potentially eligible publi-cations. The study published more recently or that contained more information was selected if duplicated data were published.

Selection criteria

For inclusion into the meta-analysis, the identi-fied studies had to meet the following criteria: (1) randomized controlled studies or observa-tional studies (case-control or cohort) focused on the clinicopathological associations of Sox2 expression in breast cancer; (2) all patients with a diagnosis of breast cancer had to be con-firmed by pathological or histological examina-tion; (3) the studies had to provide sufficient

information about the expression levels of Sox2. Studies with no clinicopathological data and articles with insufficient published data for determining an estimate of the odds ratio (OR) and 95% confidence interval (CI) were excluded from the meta-analysis.

Data extraction

All data from the included studies were extract-ed independently by two reviewers using a standardized form. The form used for data extraction documented the most relevant items, including the first author’s surname, year of publication, geographical location, age distri-butions of the participants, protein detection methods, sample size, staining patterns of Sox2, cutoff scores for the definition of positive staining, and clinicopathological parameters (tumor size, lymph node status, histological grade, TNM stage, and estrogen receptor (ER), progesterone receptor (PR), and human epider-mal growth factor receptor 2 (HER2) status (molecular subtype). Any disparities between the two reviewers were resolved by discussion and consultation with a third reviewer.

Statistical analysis

The meta-analysis was performed using Review Manager version 5.2 software (provided by The Cochrane Collaboration, Oxford, England). Given the effect value, the ORs and their 95% CIs were combined and calculated for the quan-titative aggregation of the results. Heteroge- neity across studies was evaluated by Co- chran’s Q-statistic test (P<0.1 was considered as statistically significant heterogeneity) [13]. For the existence of significant heterogeneity, a more conservative random-effects model was used to calculate the pooled estimates; other-wise a fixed-effects model was applied [14, 15]. Using Stata 12.0 software (Stata Corporation, College Station, TX, USA), the potential for pub-lication bias was assessed by Begg’s test and Egger’s linear regression test (P<0.05 was con-sidered significant) [16]. The quality of studies in meta-analysis was assessed based on the Newcastle-Ottawa Scale (NOS) (http://www.oh- ri.ca/programs/clinical_epidemiology/oxford.asp). Each study was assessed by eight ques-tions with a maximum score of 9, and studies with scores equal or above 6 were considered as high-quality, otherwise they were defined as low-quality. To guarantee the effectiveness, the subgroup analyses based on potentially signifi-

Sox2 expression and breast cancer

22384 Int J Clin Exp Med 2015;8(12):22382-22392

Table 1. Characteristics of the included studiesFirst author Year Study type Country Ethnicity Age (year) Histological type No. of patients Method Staining patterns Cut-off

scoresQuality

assessmentHuang 2014 cohort China Asian NR Mixed 552 IHC Nuclear >1% 8Nagata 2014 cohort Japan Asian 55.2 (29-87) Mixed 100 IHC Nuclear/cytoplasm scores>2 7Piva 2013 cohort Spain Caucasian NR Mixed 81 IHC Nuclear scores>2 6Abd 2014 cohort Egypt African 53.37 (35-69) Mixed 126 IHC Nuclear ≥0% 7Lengerke 2011 cohort Germany Caucasian 50-69 Mixed 86 IHC Nuclear ≥0% 7Rodriguez 2007 cohort Spain Caucasian NR Mixed 198 IHC Nuclear ≥0% 7Li 2012 cohort China Asian NR NR 269 IHC Nuclear >10% 8Qi 2012 case-control Chian Asian 55 (30-80) Mixed 65 IHC Nuclear >10% 5Xu 2013 case-control China Asian 53 (34-78) Mixed 78 IHC Nuclear/cytoplasm scores≥3 5Leis 2012 cohort Spain Caucasian NR Mixed 158 IHC Nuclear ≥0% 7NR, not reported; IHC, immunohistochemistry.

Sox2 expression and breast cancer

22385 Int J Clin Exp Med 2015;8(12):22382-22392

Sox2 expression and breast cancer

22386 Int J Clin Exp Med 2015;8(12):22382-22392

cant variables were performed when more than six studies were included in the overall analy-sis. Sensitivity analyses by sequential exclusion of each study were also conducted. All of the generated p values were two-tailed.

Results

Search results

Initially, our search strategy identified a total of 81 studies assessing the association between Sox2 expression and clinicopathological para- meters of breast cancer. After the titles and abstracts of these identified studies were screened, 51 articles were excluded. Sub- sequently, we systematically reviewed the remaining full texts and excluded another 20 articles. As a result, 10 clinical cohort studies

involving 1713 patients with breast carcinoma were included in the pooled analyses [6, 8, 11, 12, 17-22]. All ten studies utilized the immuno-histochemistry method for protein detection. The publication years of the eligible studies ranged from 2007 to 2014. Of these, 8 studies were reported in English and 2 in Chinese. The main characteristics of the included studies are displayed in Table 1.

Meta-analysis

To identify the value of Sox2 expression, 10 studies were utilized to address the associa-tions between Sox2 protein expression and clinicopathological parameters of patients with breast carcinoma. As illustrated in Figure 1 and Table 2, the pooled OR indicated a significant association between positive Sox2 expression and larger tumor size (pooled OR=2.61, 95%

Figure 1. Meta-analysis of Sox2-positive expression and the clinicopathological characteristics of patients with breast cancer.

Sox2 expression and breast cancer

22387 Int J Clin Exp Med 2015;8(12):22382-22392

CI=1.91-3.58). Similarly, the overall estimates suggested that positive Sox2 expression was significantly associated with an increased risk of lymph node metastasis (pooled OR=4.17, 95% CI=1.20-14.45), and high tumor histologi-cal grade (pooled OR=2.28, 95% CI=1.72-3.03). Moreover, a borderline significance between positive Sox2 expression and high tumor stage was also revealed (pooled OR=2.94, 95% CI=0.90-9.65). However, no significant associa-tions between Sox2 expression and ER, PR, and HER2 status were found in breast cancer patients (pooled OR=0.99, 95% CI=0.38-2.60; OR=0.89, 95% CI=0.34-2.36; OR=1.36, 95% CI=0.94-1.97, respectively). When considering the subtype of breast cancer, positive expres-sion of Sox2 was found to be significantly asso-ciated with the biologically aggressive triple-negative phenotype (pooled OR=2.64, 95% CI=1.11-6.29). Analysis of clinicopathological parameters revealed no obvious evidence of asymmetry in the funnel plots for publication bias (Figure 2), which was also supported by the Egger’s test (tumor size, P=0.24; histologi-cal grade, P=0.185; TNM stage, P=0.789; lymph node metastasis, P=0.053; ER status, P=0.515; PR status, P=0.468; HER2 status, P=0.829; subtype, P=0.121).

As shown in Table 2, the subgroup analyses based on ethnicity, sample size and quality were also conducted when more than six stud-ies were included in the overall analyses regard-ing the concerned variables. As a result, the association between Sox2 expression and tumor size remained significant regardless of the ethnicity, sample size and quality variations (all P<0.05). Similar association was also observed regarding tumor histological grade in all subgroup analyses (all P<0.05) except for the lack of the relationship in studies with low quality (P>0.05). Unfortunately, no significant association regarding lymph node metastasis was revealed in any subgroup analyses except for that in studies with low quality (P<0.05), however, the results was presented with obvi-ous heterogeneity. Moreover, the stratification analysis by ethnicity and sample size also failed to show any significant association of Sox2 expression and HER-2 status (all P<0.05).

Sensitivity analysis

To examine the stability of overall estimates, sensitivity analysis was performed by sequen-

tially eliminating studies one by one. The remov-al of one study each turn showed no significant variation in overall estimates regarding the tumor size, tumor histological grade, ER and HER-2 status, suggesting the robustness of these results. Furthermore, we found a slight fluctuation of the p-value around 0.05 in the sensitivity analysis. Nevertheless, a significant association was suggested by most results of sequential omission. However, the overall esti-mate for the association of Sox2 expression and lymph node metastasis was significantly altered by excluding the studies by Li et al. [19] and Xu et al. [21], respectively. Similarly, the significance of pooled OR was excessively affected regarding the tumor stage by omitting the study by Nagata et al. [17] and regarding PR status by omitting the study by Abd et al. [6], suggesting the necessity to validate these associations with more well-designed studies.

Discussion

To the best of our knowledge, the current meta-analysis is the first study to systematically esti-mate the associations between Sox2 expres-sion and the clinicopathological characteristics of breast cancer. Our pooled results of 10 stud-ies involving 1713 cases provide compelling evidence of a significant positive correlation between Sox2 protein expression and increas- ed tumor size, higher histological grade, lymph node metastasis, and the highly aggressive tri-ple-negative phenotype of breast cancer.

As transcription factors, all Sox proteins, includ-ing Sox2, do not possess sufficient affinities for DNA binding to be able to activate or repress target gene expression [23]. Instead, it is cur-rently generally accepted that the regulatory effects of the Sox2 are mediated through inter-actions with partner proteins such as cytokera-tin (CK) 5/6, epidermal growth factor receptor (EGFR), cyclin D1, the epithelial mesenchymal transition-related marker vimentin, and several other proteins and pathways [8, 19, 24, 25]. Although the molecular basis of Sox2 involve-ment in the development of breast cancer remains largely unknown, accumulative evi-dence indicates that it may play roles in the regulation of cell fate determination, differenti-ation, proliferation, and neoplastic transforma-tion [4]. Chen et al. found that the expression of Sox2 was significantly higher in 56 breast can-cer samples compared to in 19 normal tissues,

Sox2 expression and breast cancer

22388 Int J Clin Exp Med 2015;8(12):22382-22392

Table 2. Meta-analysis results of the association between Sox2 expression and breast cancerVariables Number of

studies Overall OR (95% CI)P-value Heterogeneity OR (95% CI) of subgroup analysis

Ph I2 Ethnicity (Asian/Caucasian) Sample size (≥100/<100) Quality (≥6/<6)Tumor size 7 2.61 (1.91-3.58) <0.001 0.76 0% 2.94 (1.98-4.37)/2.08 (1.22-3.54) 3.10 (2.08-4.62)/1.93 (1.15-3.23) 2.71 (1.92-3.83)/2.17 (1.02-4.64)

Histological grade 8 2.28 (1.72, -3.03) <0.001 0.28 19% 2.16 (1.50-3.10)/2.42 (1.37-4.27) 1.98 (1.43-2.74)/3.46 (1.34-8.97) 2.05 (1.51-2.78)/3.81 (0.79-18.41)

Tumor stage 4 2.94 (0.90-9.65) 0.07 0.06 60% - - -

LNM 6 4.17 (1.20-14.45) 0.02 <0.001 91% 7.49 (0.99-56.89)/0.86 (0.29-2.54) 6.35 (0.61-66.34)/2.99 (0.81-11.02) 3.72 (0.68-20.39)/5.84 (2.63-12.95)

ER status 5 0.99 (0.38-2.60) 0.98 <0.001 85% - - -

PR status 4 0.89 (0.34-2.36) 0.81 <0.001 86% - - -

HER-2 status 6 1.36 (0.94-1.97) 0.1 0.88 0% 1.27 (0.76-2.13)/1.16 (0.54-2.48) 1.35 (0.90-2.02)/1.42 (0.58-3.52) -

Subtype 5 2.64 (1.11-6.30) 0.03 0.01 69% - - -LNM, lymph node metastasis; Ph, P-value of heterogeneity.

Sox2 expression and breast cancer

22389 Int J Clin Exp Med 2015;8(12):22382-22392

Sox2 expression and breast cancer

22390 Int J Clin Exp Med 2015;8(12):22382-22392

and a similar result was observed in an in vitro study, suggesting a role of Sox2 in tumorigene-sis [23]. Based on our results in the present meta-analysis, we conclude that patients with high levels of Sox2 protein expression in their tumors are more likely to develop larger tumors. This may be explained by the previously sug-gested mechanism that overexpression of Sox2 in MCF-7 breast cancer cells resulted in enhanced cell proliferation and tumorigenesis through upregulation of cyclin D1, and by sub-sequently facilitating G1/S transition of the cell cycle [23]. Moreover, in agreement with most previous studies demonstrating that positive Sox2 expression contributes to an increased risk of lymph node metastasis [6, 19-21], this association was confirmed in our pooled analy-ses, although we failed to represent this asso-ciation in the subgroup analyses, which may be due to the considerable heterogeneity. In this regard, Li et al. demonstrated that Sox2 results in increased metastasis of breast and prostate cancer cells by promoting epithelial-to-mesen-chymal transition through Wnt/β-catenin sig-naling [19], indicating a potential underlying mechanism for the role of Sox2 in breast can-cer metastasis. Furthermore, as the Sox-induced generant repression of differentiation into neurons [7], a previous study revealed that the expression of embryonic transcriptional factors, including Sox2, may be highly associ-ated with less differentiated breast cancer [26]. Similarly, Rodriguez-Pinilla et al. reported that higher Sox2 expression was more com-monly observed in basal cell-like breast carci-nomas compared to other subtypes, and that it strongly correlated with CK5/6, EGFR, and vimentin immunoreactivity, suggesting that Sox2 may play a role in conferring a less differ-entiated and a more aggressive phenotype of breast cancer [8]. In keeping with their findings, our combined results revealed that positive Sox2 expression was significantly associated with a high tumor grade and the triple-negative subtype, altogether indicating a potential role of Sox2 in the pathological diagnosis, progno-sis, and clinical procedures of breast cancer.

The statistical procedures used in the present meta-analysis may account for the varying degrees of reliability across individual studies by weighting the effect size from any one study

by its sample size [27]. Although our systematic review was robust in identifying the significance of Sox2 in breast cancer, several limitations still need to be addressed. First, the present meta-analysis was restricted to studies pub-lished in English and Chinese only, which may cause selection bias, however, studies report-ed in other languages are not usually available for investigators. Second, the immunostaining cutoff points and methodological designs were arbitrarily selected and varied between the analyzed studies, and variability in protein expression assessment may be a cause of potential bias, which would limit our confidence in drawing conclusions. Third, the histological type of breast cancer may contribute to the studied associations [18], as it was not unified in the included studies of the meta-analysis, which may also potentially influence the results. Lastly, Sox2 usually exerts its transcription reg-ulation function through interactions with part-ner proteins [4, 28], and analyses of any poten-tial interactions between these other proteins and Sox2 in breast cancer were neglected due to the absence of original data. Additional well-designed studies with a unified definition in terms of the protein expression assessment, uniform cases, and larger sample sizes are needed to present more reliable results.

In summary, the present meta-analysis pro-vides a relative outline of Sox2 and a number of common clinicopathological parameters, such as tumor size, differentiation, lymph node sta-tus, and molecular subtypes, in patients with breast cancer. Based on our results, we believe that the detection of Sox2 expression may be of great value in determining the diagnosis and prognosis of breast cancer patients. However, given the limitations of our meta-analysis, the findings presented herein warrant future inves-tigations to validate the diagnostic and prog-nostic value of Sox2 using well-designed stud-ies and larger sample sizes.

Disclosure of conflict of interest

None.

Address correspondence to: Li Li, Department of Nursing, Renmin Hospital, Hubei University of

Figure 2. Funnel plot of publication biases on the relationships between Sox2-positive expression and the clinico-pathological characteristics of patients with breast cancer.

Sox2 expression and breast cancer

22391 Int J Clin Exp Med 2015;8(12):22382-22392

Medicine, 39 Chaoyang Road, Shiyan 442000, Hubei, China. Tel: +86-719-8637036; Fax: +86-719-8637036; E-mail: LiLishiyan@126.com

References

[1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90.

[2] Piva M, Domenici G, Iriondo O, Rabano M, Si-moes BM, Comaills V, Barredo I, Lopez-Ruiz JA, Zabalza I, Kypta R, Vivanco M. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med 2014; 6: 66-79.

[3] Al-Hajj M, Clarke MF. Self-renewal and solid tu-mor stem cells. Oncogene 2004; 23: 7274-82.

[4] Al-Dhfyan A. Embryonic signature in breast cancers; Pluripotency roots of cancer stem cells. Saudi Pharm J 2013; 21: 229-32.

[5] Raof NA, Mooney BM, Xie Y. Bioengineering embryonic stem cell microenvironments for the study of breast cancer. Int J Mol Sci 2011; 12: 7662-91.

[6] Abd EN, Abd ED. Clinicopathologic implications of epcam and sox2 expression in breast can-cer. Clin Breast Cancer 2014; 14: e1-9.

[7] Graham V, Khudyakov J, Ellis P, Pevny L. Sox2 functions to maintain neural progenitor identi-ty. Neuron 2003; 39: 749-65.

[8] Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G, Rodriguez-Gil Y, Martinez MA, Hernandez L, Hardisson D, Reis-Filho JS, Palacios J. Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 2007; 20: 474-81.

[9] Sanada Y, Yoshida K, Ohara M, Oeda M, Koni-shi K, Tsutani Y. Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor sox2: compari-son of expression patterns between invasive components and cancerous or nonneoplastic intraductal components. Pancreas 2006; 32: 164-70.

[10] Gure AO, Stockert E, Scanlan MJ, Keresztes RS, Jager D, Altorki NK, Old LJ, Chen YT. Sero-logical identification of embryonic neural pro-teins as highly immunogenic tumor antigens in small cell lung cancer. Proc Natl Acad Sci U S A 2000; 97: 4198-203.

[11] Huang YH, Luo MH, Ni YB, Tsang JY, Chan SK, Lui PC, Yu AM, Tan PH, Tse GM. Increased sox2 expression in less differentiated breast carci-nomas and their lymph node metastases. His-topathology 2014; 64: 494-503.

[12] Piva M, Domenici G, Iriondo O, Rabano M, Si-moes BM, Comaills V, Barredo I, Lopez-Ruiz JA, Zabalza I, Kypta R, Vivanco M. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med 2014; 6: 66-79.

[13] Zintzaras E, Ioannidis JP. Hegesma: genome search meta-analysis and heterogeneity test-ing. Bioinformatics 2005; 21: 3672-3.

[14] Higgins JP, Thompson SG. Quantifying hetero-geneity in a meta-analysis. Stat Med 2002; 21: 1539-58.

[15] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analy-ses. BMJ 2003; 327: 557-60.

[16] Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to de-tect publication bias in meta-analysis. JAMA 2006; 295: 676-80.

[17] Nagata T, Shimada Y, Sekine S, Hori R, Matsui K, Okumura T, Sawada S, Fukuoka J, Tsukada K. Prognostic significance of nanog and klf4 for breast cancer. Breast Cancer 2014; 21: 96-101.

[18] Lengerke C, Fehm T, Kurth R, Neubauer H, Scheble V, Muller F, Schneider F, Petersen K, Wallwiener D, Kanz L, Fend F, Perner S, Bareiss PM, Staebler A. Expression of the embryonic stem cell marker sox2 in early-stage breast carcinoma. BMC Cancer 2011; 11: 42-51.

[19] Li X, Xu Y, Chen Y, Chen S, Jia X, Sun T, Liu Y, Li X, Xiang R, Li N. Sox2 promotes tumor metas-tasis by stimulating epithelial-to-mesenchymal transition via regulation of wnt/beta-catenin signal network. Cancer Lett 2013; 336: 379-89.

[20] Qi HJ, Guan DS, Wei FQ. The expression and significance of sox2, er and pr in breast carci-noma. Jilin Medicine 2012; 33: 3604-5.

[21] Xu ZH, Yao H. The expressions and significance of sox2, oct4, β-catenin and p-120 catenin pro-tein in breast carcinoma. Chinese Remedies & Clinics 2013; 13: 737-9.

[22] Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K, Pandiella A, Rezola R, Martin AG. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012; 31: 1354-65.

[23] Chen Y, Shi L, Zhang L, Li R, Liang J, Yu W, Sun L, Yang X, Wang Y, Zhang Y, Shang Y. The mo-lecular mechanism governing the oncogenic potential of sox2 in breast cancer. J Biol Chem 2008; 283: 17969-78.

[24] Wilson M, Koopman P. Matching sox: partner proteins and co-factors of the sox family of transcriptional regulators. Curr Opin Genet Dev 2002; 12: 441-6.

[25] Kamachi Y, Uchikawa M, Kondoh H. Pairing sox off: with partners in the regulation of embry-onic development. Trends Genet 2000; 16: 182-7.

[26] Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tu-mors. Nat Genet 2008; 40: 499-507.

Sox2 expression and breast cancer

22392 Int J Clin Exp Med 2015;8(12):22382-22392

[27] Arnqvist G, Wooster D. Meta-analysis: synthe-sizing research findings in ecology and evolu-tion. Trends Ecol Evol 1995; 10: 236-40.

[28] Wilson M, Koopman P. Matching sox: partner proteins and co-factors of the sox family of

transcriptional regulators. Curr Opin Genet Dev 2002; 12: 441-6.