Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma
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Qing-Yun Chong1, Ming-Liang You1,2, Vijay Pandey1, Arindam Banerjee1, Yi-Jun Chen1,2, Han-Ming Poh1,2, Mengyi Zhang1,2, Lan Ma3, Tao Zhu4,5, Salundi Basappa6, Liang Liu7,8 and Peter E. Lobie1,2,3,9
1Cancer Science Institute of Singapore, National University of Singapore, Singapore
2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3Tsinghua Berkeley Shenzhen Institute, Tsinghua University Graduate School at Shenzhen, Shenzhen, China
4Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
5The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
6Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Bangalore, India
7Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
8Department of Radiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
9National University Cancer Institute, Singapore
Peter E. Lobie, email: [email protected]
Liang Liu, email: [email protected]
Keywords: trefoil factor 3, breast cancer, HER2, trastuzumab resistance, estrogen receptor
Received: November 17, 2016 Accepted: May 10, 2017 Published: June 09, 2017
HER2+/ER+ breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers. The bidirectional crosstalk between HER2 and estrogen receptor (ER) in HER2+/ER+ breast cancer contributes to resistance towards both anti-estrogens and HER2-targeted therapies. TFF3 promotes breast cancer progression and has been implicated in anti-estrogen resistance in breast cancer. Herein, we investigated the cross-regulation between HER2 and estrogen-responsive TFF3, and the role of TFF3 in mediating trastuzumab resistance in HER2+/ER+ breast cancer. TFF3 expression was decreased by HER2 activation, and increased by inhibition of HER2 with trastuzumab in HER2+/ER+ breast cancer cells, partially in an ERα-independent manner. In contrast, the forced expression of TFF3 activated the entire HER family of receptor tyrosine kinases (HER1-4). Hence, HER2 negatively regulates its own signalling through the transcriptional repression of TFF3, while trastuzumab inhibition of HER2 results in increased TFF3 expression to compensate for the loss of HER2 signalling. In HER2+/ER+ breast cancer cells with acquired trastuzumab resistance, TFF3 expression was markedly upregulated and associated with a corresponding decrease in HER signalling. siRNA mediated depletion or small molecule inhibition of TFF3 decreased the survival and growth advantage of the trastuzumab resistant cells without re-sensitization to trastuzumab. Furthermore, TFF3 inhibition abrogated the enhanced cancer stem cell-like behaviour in trastuzumab resistant HER2+/ER+ breast cancer cells. Collectively, TFF3 may function as a potential biomarker and therapeutic target in trastuzumab resistant HER2+/ER+ breast cancer.
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