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ERβ1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer

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Abstract

In contrast to the well-established role of estrogen receptor alpha (ERα) in breast cancer, the significance of estrogen receptor beta (ERβ) remains controversial, especially in triple-negative breast cancer (TNBC). We sought to investigate the clinical importance of wild-type ERβ (ERβ1) in TNBC based on a large population, and to explore the potential molecular pathways involved in. A total of 571 patients with invasive TNBC undergoing curative surgery were included in this study. Immunohistochemical staining for ERβ1, pAKT, PTEN, pERK, β-catenin, EGFR, p53, and E-cadherin was performed on tissue microarrays. Prognostic determinants for overall survival (OS) and disease-free survival (DFS), as well as the risk factors for distant metastasis-free survival (DMFS) and locoregional recurrence-free survival, were evaluated in univariate and multivariate analyses. Overexpression of ERβ1 was detected in 30.4 % of tumor samples. Patients with ERβ1 tended to be postmenopausal, and less likely to develop lymphatic metastasis. Multivariate analysis demonstrated that ERβ1 predicted a better OS, DFS, and DMFS independently. Regarding other biomarkers, only pAKT was identified as an independent negative predictor for survival. Additionally, ERβ1 expression was inversely associated with pAKT and the loss of PTEN. Notably, further survival analysis according to status of ERβ1/pAKT indicated that ERβ1(+)/pAKT(−) predicted the most favorable prognosis for TNBC. On the contrary, ERβ1(−)/pAKT(+) was associated with the worst outcomes. In summary, our findings indicate that ERβ1 independently predicts a better prognosis for TNBC and potentially interacts with the PTEN/PI3K/pAKT pathway. The role of ERβ1-specific agonists combined with the inhibitors of pAKT merits further investigation.

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Acknowledgments

We would like to thank the patients that participated in this study. This work was supported by the National Natural Science Foundation of China (81402183), the Priming Scientific Research Foundation for the Junior Teachers of Medicine in Sun Yat-sen University (13ykpy48), the Talents Scheme in Sun Yat-Sen University Cancer Center (2014–13) and the Medical Scientific Research Foundation of Guangdong Province (B2013143).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 Dongfeng East Road, Yuexiu District, Guangzhou, 510060, China

    Jin Wang, Hailin Tang, Jun Tang, Cailu Song & Xiaoming Xie

  2. Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Yuexiu District, Guangzhou, 510060, China

    Chao Zhang & Keming Chen

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  1. Jin Wang
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  2. Chao Zhang
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  3. Keming Chen
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  4. Hailin Tang
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  5. Jun Tang
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  6. Cailu Song
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  7. Xiaoming Xie
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Correspondence to Jin Wang or Xiaoming Xie.

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Jin Wang, Chao Zhang and Hailin Tang are co-first authors.

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Wang, J., Zhang, C., Chen, K. et al. ERβ1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer. Breast Cancer Res Treat 152, 255–269 (2015). https://doi.org/10.1007/s10549-015-3467-3

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