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Theranostics 2019; 9(23):6840-6855. doi:10.7150/thno.36338 This issue Cite

Research Paper

CapG promotes resistance to paclitaxel in breast cancer through transactivation of PIK3R1/P50

Yayun Chi^1,3*, Jingyan Xue^1*, Sheng Huang^1*, Bingqiu Xiu^1*, Yonghui Su¹, Wei Wang^3,4, Rong Guo¹, Lei Wang², Lun Li¹, Zhiming Shao¹, Wei Jin¹, Zhaohui Wu^3,4✉, Jiong Wu^1,5✉

1. Department of Breast Surgery, Breast Cancer Institute, Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
2. Department of Pathology, Fudan University, Shanghai Cancer Center, Shanghai, China.
3. Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
4. Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
5. Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
*These authors contributed equally to this work.

✉ Corresponding author: Jiong Wu, Department of Breast Surgery, Breast Cancer Institute, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. email: wujiong1122sina.com, Tel: 86-21-64175590, Fax: 86-21-64031696; Zhaohui Wu, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, email: zwu6edu, Tel: 901-448-2612, Fax: 901-448-3910. More

Abstract

Background: Chemotherapy resistance is a major problem in breast cancer treatment and a leading cause of mortality in breast cancer patients. Biomarkers for chemotherapy resistance is under investigation.

Methods: Paclitaxel resistant cells were established and subjected to RNA sequencing. Analysis combined with two additional RNA-seq datasets was conducted. CapG expression in patients with adjuvant chemotherapy was studied in breast cancer resection specimens using IHC and related to pathological response and disease-free survival. Paclitaxel resistance was assessed by half-maximal inhibitory concentrations (IC50) and a mouse xenograft model.

Results: Increased expression of actin-binding protein CapG strongly correlated with the resistance to paclitaxel chemotherapy and decreased probability to achieve pathological complete response in breast cancer patients. Overexpressing CapG significantly enhanced paclitaxel resistance in breast cancer cells and xenograft tumors. High CapG level also significantly correlated with shorter relapse-free survival as well as hyper-activation of PI3K/Akt signaling in breast cancer patients. Mechanistically, CapG enhanced PIK3R1 expression which led to increased PI3K/Akt activation. Unexpectedly, CapG was found to bind to the variant-specific promoter of PIK3R1/P50 and directly enhance its transcription. We also identified p300/CBP as a transcriptional coregulator of CapG, which is recruited to PIK3R1 promoter through interaction with CapG, thereby increasing PIK3R1/P50 transcription by enhancing histone H3K27 acetylation. Consistently, inhibiting p300/CBP substantially decreased CapG-dependent upregulation of PIK3R1/P50 and subsequent PI3K/Akt activation, resulting in increased sensitivity to paclitaxel treatment in breast cancer cells.

Conclusion: High CapG levels may predict poor paclitaxel response in breast cancer patients. Targeting CapG-mediated hyperactivation of PI3K/Akt pathway may mitigate resistance to chemotherapy in breast cancer.

Keywords: breast cancer, chemotherapy resistance, CapG, PIK3R1, CBP/P300

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