Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis

doi:10.1097/MD.0000000000004085

Review

. 2016 Jul;95(27):e4085.

doi: 10.1097/MD.0000000000004085.

Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis

Han-Xiao Xu¹, Kong-Ju Wu, Yi-Jun Tian, Qian Liu, Na Han, Xue-Lian He, Xun Yuan, Gen Sheng Wu, Kong-Ming Wu

Affiliations

Affiliation

¹ Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Nursing School of Pingdingshan University, Pingdingshan, Henan Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei, People's Republic of China Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.

PMID: 27399099
PMCID: PMC5058828
DOI: 10.1097/MD.0000000000004085

Review

Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis

Han-Xiao Xu et al. Medicine (Baltimore). 2016 Jul.

. 2016 Jul;95(27):e4085.

doi: 10.1097/MD.0000000000004085.

Authors

Han-Xiao Xu¹, Kong-Ju Wu, Yi-Jun Tian, Qian Liu, Na Han, Xue-Lian He, Xun Yuan, Gen Sheng Wu, Kong-Ming Wu

Affiliation

¹ Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Nursing School of Pingdingshan University, Pingdingshan, Henan Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei, People's Republic of China Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.

PMID: 27399099
PMCID: PMC5058828
DOI: 10.1097/MD.0000000000004085

Abstract

Sineoculis homeobox homolog (SIX) family proteins, including SIX1, SIX2, SIX3, SIX4, SIX5, and SIX6, have been implicated in the initiation and progression of breast cancer, but the role of each member in breast tumor is not fully understood. We conducted a systematic review and meta-analysis to evaluate the association between the mRNA levels of all 6 members and clinic-pathological characteristics and clinical outcome of breast cancer patients based on the PRISMA statement criteria.ArrayExpress and Oncomine were searched for eligible databases published up to December 10, 2015. The association between the mRNA expression of SIX family members and clinic-pathological features and prognosis was measured by the odds ratio (OR), hazard ratio (HR), and the corresponding 95% confidence interval (CI), respectively. All statistical analyses were performed using STATA software.In total, 20 published Gene Expression Omnibus (GEO) databases with 3555 patients were analyzed. Our analysis revealed that patients with SIX1 overexpression had worse overall survival (OS) (HR: 1.28, 95% CI: 1.03-1.58) and shorter relapse-free survival (RFS) (HR: 1.28, 95% CI: 1.05-1.56), and much worse prognosis for luminal breast cancer patients with SIX1 overexpression (OS: HR: 1.64, 95% CI: 1.13-2.39; RFS: HR: 1.43, 95% CI: 1.06-1.93). We found that patients with higher SIX2 level had shorter time to both relapse and metastasis. However, high SIX3 mRNA level was a protective factor for OS and RFS of basal-like breast cancer patients.Our study suggested that members of SIX family played distinct roles in breast cancer. Detailed analysis of the expression of the SIX family members might provide useful information to predict breast cancer progression and prognosis.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

**Figure 1**
Flow diagram of article selection.

**Figure 2**
Forest plot of odds ratio (OR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and breast cancer risks in comparison to normal breast tissues. (B). Association between the mRNA expression of *SIX2* and breast cancer risks in comparison to normal breast tissues. (C). Association between the mRNA expression of *SIX3* and breast cancer risks in comparison to normal breast tissues. (D). Association between the mRNA expression of *SIX4* and breast cancer risks in comparison to normal breast tissues.

**Figure 3**
Forest plot of odds ratio (OR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and histological grade of breast cancer. (B). Association between the mRNA expression of *SIX2* and histological grade of breast cancer. (C). Association between the mRNA expression of *SIX3* and histological grade of breast cancer.

**Figure 4**
Forest plot of odds ratio (OR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and ER status of breast cancer. (B). Association between the mRNA expression of *SIX2* and ER status of breast cancer. (C). Association between the mRNA expression of *SIX3* and ER status of breast cancer. (D). Association between the mRNA expression of *SIX1* and PR status of breast cancer. (E). Association between the mRNA expression of *SIX2* and PR status of breast cancer. (F). Association between the mRNA expression of *SIX3* and PR status of breast cancer.

**Figure 5**
Forest plot of odds ratio (OR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and basal-like breast cancer in comparison to luminal subtype. (B). Association between the mRNA expression of *SIX2* and basal-like breast cancer in comparison to luminal subtype. (C). Association between the mRNA expression of *SIX3* and basal-like breast cancer in comparison to luminal subtype.

**Figure 6**
Forest plot of hazard radio (HR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and OS of breast cancer. (B). Association between the mRNA expression of *SIX1* and RFS of breast cancer. (C). Association between the mRNA expression of *SIX1* and MFS of breast cancer. (D). Association between the mRNA expression of *SIX2* and OS of breast cancer. (E). Association between the mRNA expression of *SIX2* and RFS of breast cancer. (F). Association between the mRNA expression of *SIX2* and MFS of breast cancer.

**Figure 7**
Forest plot of hazard radio (HR). CI = confidence interval. (A). Association between the mRNA expression of *SIX1* and OS of luminal breast cancer. (B). Association between the mRNA expression of *SIX1* and RFS of luminal breast cancer. (C). Association between the mRNA expression of *SIX6* and OS of luminal breast cancer. (D). Association between the mRNA expression of *SIX6* and RFS of luminal breast cancer. (E). Association between the mRNA expression of *SIX3* and OS of basal-like breast cancer. (F). Association between the mRNA expression of *SIX3* and RFS of basal-like breast cancer.

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References

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1. Makki J. Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol 2015; 8:23–31. - PMC - PubMed
1. Radenkovic S, Milosevic Z, Konjevic G, et al. Lactate dehydrogenase, catalase, and superoxide dismutase in tumor tissue of breast cancer patients in respect to mammographic findings. Cell Biochem Biophys 2013; 66:287–295. - PubMed
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[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7–30. - PubMed

[2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7–30. - PubMed

[3] Makki J. Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol 2015; 8:23–31. - PMC - PubMed

[4] Makki J. Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol 2015; 8:23–31. - PMC - PubMed

[5] Radenkovic S, Milosevic Z, Konjevic G, et al. Lactate dehydrogenase, catalase, and superoxide dismutase in tumor tissue of breast cancer patients in respect to mammographic findings. Cell Biochem Biophys 2013; 66:287–295. - PubMed

[6] Radenkovic S, Milosevic Z, Konjevic G, et al. Lactate dehydrogenase, catalase, and superoxide dismutase in tumor tissue of breast cancer patients in respect to mammographic findings. Cell Biochem Biophys 2013; 66:287–295. - PubMed

[7] Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet 2005; 6:893–904. - PubMed

[8] Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet 2005; 6:893–904. - PubMed

[9] Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 2003; 426:247–254. - PubMed

[10] Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 2003; 426:247–254. - PubMed

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Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis

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Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis

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