Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.18431
Title: Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma
Authors: Chong, Q.-Y 
You, M.-L 
Pandey, V 
Banerjee, A 
Chen, Y.-J
Poh, H.-M
Zhang, M
Ma, L
Zhu, T
Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Bangalore, India
Liu, L
Lobie, P.E 
Keywords: epidermal growth factor receptor
epidermal growth factor receptor 2
estrogen receptor
estrogen receptor alpha
her 1 protein
her 3 protein
her 4 protein
small interfering RNA
trastuzumab
trefoil factor 3
tumor marker
unclassified drug
Article
breast cancer cell line
breast carcinoma
cancer growth
cancer resistance
cancer stem cell
cancer survival
cell function
controlled study
disease association
disease marker
drug sensitization
drug targeting
estrogen receptor positive breast cancer
human
human cell
immunoblotting
polymerase chain reaction
protein expression
protein family
protein function
regulatory mechanism
signal transduction
transcription regulation
upregulation
Western blotting
Issue Date: 2017
Publisher: Impact Journals LLC
Citation: Chong, Q.-Y, You, M.-L, Pandey, V, Banerjee, A, Chen, Y.-J, Poh, H.-M, Zhang, M, Ma, L, Zhu, T, Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Bangalore, India, Liu, L, Lobie, P.E (2017). Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma. Oncotarget 8 (43) : 74188-74208. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.18431
Abstract: 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 estrogenresponsive 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. © Chong et al.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174441
ISSN: 1949-2553
DOI: 10.18632/oncotarget.18431
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