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Sequential combination of docetaxel with a SHP-1 agonist enhanced suppression of p-STAT3 signaling and apoptosis in triple negative breast cancer cells

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Abstract

Triple negative breast cancer (TNBC) is an aggressive cancer for which prognosis remains poor. Combination therapy is a promising strategy for enhancing treatment efficacy. Blockade of STAT3 signaling may enhance the response of cancer cells to conventional chemotherapeutic agents. Here we used a SHP-1 agonist SC-43 to dephosphorylate STAT3 thereby suppressing oncogenic STAT3 signaling and tested it in combination with docetaxel in TNBC cells. We first analyzed messenger RNA (mRNA) expression of SHP-1 gene (PTPN6) in a public TNBC dataset (TCGA) and found that higher SHP-1 mRNA expression is associated with better overall survival in TNBC patients. Sequential combination of docetaxel and SC-43 in vitro showed enhanced anti-proliferation and apoptosis associated with decreased p-STAT3 and decreased STAT3-downstream effector cyclin D1 in the TNBC cell lines MDA-MB-231, MDA-MB-468, and HCC-1937. Ectopic expression of STAT3 reduced the increased cytotoxicity induced by the combination therapy. In addition, this sequential combination showed enhanced SHP-1 activity compared to SC-43 alone. Furthermore, the combination treatment-induced apoptosis was attenuated by small interfering RNA (siRNA) against SHP-1 or by ectopic expression of SHP-1 mutants that caused SC-43 to lose its SHP-1 agonist capability. Moreover, combination of docetaxel and SC-43 showed enhanced tumor growth inhibition compared to single-agent therapy in mice bearing MDA-MB-231 tumor xenografts. Our results suggest that the novel SHP-1 agonist SC-43 enhanced docetaxel-induced cytotoxicity by SHP-1 dependent STAT3 inhibition in human triple negative breast cancer cells. TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3.

Key messages

  • TNBC patients with high SHP-1 expressions show better survival.

  • Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3.

  • SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination.

  • Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3.

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Author information

Author notes

  1. Chun-Yu Liu and Kuen-Feng Chen contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan

    Chun-Yu Liu, Tzu-Ting Huang, Hsiu-Ping Yang, Chia-Han Lee, Ka-Yi Lau, Wen-Chun Tsai, Chia-Yun Wu & Ming-Huang Chen

  2. School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei, 112, Taiwan

    Chun-Yu Liu, Chun-Teng Huang, Chia-Yun Wu, Ming-Huang Chen & Ling-Ming Tseng

  3. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan

    Chun-Yu Liu, Chia-Yun Wu & Ming-Huang Chen

  4. Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan

    Chun-Yu Liu, Tzu-Ting Huang & Ling-Ming Tseng

  5. Department of Medical Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan

    Kuen-Feng Chen & Tzu-I Chao

  6. National Taiwan University College of Medicine, No. 1 Sec. 1, Jen-Ai Road, Taipei, 100, Taiwan

    Kuen-Feng Chen

  7. Department of Pathology, Show Chwan Memorial Hospital, No. 542, Sec. 1, Chung-Shan Rd, Changhua City, 500, Taiwan

    Pei-Yi Chu

  8. School of Medicine, Fu Jen Catholic University, No. 510, Zhong-zheng Rd., Xin-zhuang Dist, New Taipei City, 24205, Taiwan

    Pei-Yi Chu

  9. Division of Hematology and Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, No. 145, Zhengzhou Rd., Datong Dist, Taipei, 10341, Taiwan

    Chun-Teng Huang

  10. Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan

    Wan-Lun Wang & Ling-Ming Tseng

  11. Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei, 112, Taiwan

    Jung-Chen Su & Chung-Wai Shiau

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  1. Chun-Yu Liu
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  2. Kuen-Feng Chen
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Correspondence to Ling-Ming Tseng.

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The authors declare no conflicts of interest.

Research involving animals

The animal study was approved and all experimental procedures using these mice were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee of Taipei Veterans General Hospital.

Funding information

This work was supported by grants from the Taiwan Clinical Oncology Research Foundation; the Yen Tjing Ling Medical Foundation (CI-104-07); the Ministry of Science and Technology, Taiwan (MOST 103-2811-B-002-157, MOST 103-2325-B-075-002, MOST 104-2628-B-075-001-MY3, MOST 104-2811-B-002-030, MOST 104-2321-B-010-017, 105-2314-B-002-190-MY2); the National Health Research Institutes, Taiwan (NHRI-EX106-10608BI); Yang-Ming Branch of Taipei City Hospital (104 No. 35, M-1A00-B-B17-35); Taipei Veterans General Hospital (V103C-141, V104C-151, V105C-067); the TVGH-NTUH Joint Research Program (VN103-08, and VN105-09) from Taipei Veterans General Hospital and National Taiwan University Hospital, and from the Ministry of Health and Welfare, Executive Yuan, Taiwan (MOHW105-TDU-B-211-134-003, MOHW104-TDU-B-211-124-001 for the Center of Excellence, and MOHW103TDU-212-114-002, MOHW106-TDU-B-211-144-003 for Cancer Research at Taipei Veterans General Hospital). This study was also partially supported by the Chong Hin Loon Memorial Cancer and the Biotherapy Research Center of National Yang-Ming University, Taipei, Taiwan.

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Liu, CY., Chen, KF., Chao, TI. et al. Sequential combination of docetaxel with a SHP-1 agonist enhanced suppression of p-STAT3 signaling and apoptosis in triple negative breast cancer cells. J Mol Med 95, 965–975 (2017). https://doi.org/10.1007/s00109-017-1549-x

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