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 ERa-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.
[1]Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore;
[2]Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore;
[3]Tsinghua Univ, Tsinghua Berkeley Shenzhen Inst, Grad Sch Shenzhen, Shenzhen, Peoples R China;
[4]Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei, Anhui, Peoples R China;
[5]Univ Sci & Technol China, Sch Life Sci, Hefei, Anhui, Peoples R China;
[6]Univ Sci & Technol China, CAS Key Lab Innate Immun & Chron Dis, Sch Life Sci, Hefei, Anhui, Peoples R China;
[7]Bangalore Univ, Dept Chem, Lab Chem Biol, Cent Coll Campus, Bangalore, Karnataka, India;
[8]Fudan Univ, Shanghai Canc Ctr, Dept Oncol, Shanghai, Peoples R China;
[9]Fudan Univ, Shanghai Canc Ctr, Dept Radiol, Shanghai, Peoples R China;
[10]Natl Univ Canc Inst, Singapore, Singapore
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