Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma

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 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.

Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK

“…The protein expression of TFF3 was also observed to be higher in spheroid compared to monolayer culture ( Figure 3B). This data is consistent with previous findings that TFF3 promotes CSC-like behaviour in trastuzumab resistant mammary carcinoma cells and hepatocellular carcinoma cells [26,27]. Caco2 cells with forced expression of TFF3 exhibited significantly increased size and number of spheroids when compared with -Vec cells ( Figure 3C).…”

“…Hence, these observations support the specificity of AMPC to TFF3. As expected [19,26], AMPC treatment significantly reduced the total cellular levels of TFF3 in SW620 and Caco2 cells in a dose dependent manner ( Figure 4B and Figure S3B). Consistent with the effect of siRNA-mediated depletion of TFF3, inhibition of TFF3 by AMPC decreased cell proliferation in CMS4 CRC cells, as shown by decrease in the S-phase population compared with dimethyl sulfoxide (DMSO)-treated control cells ( Figure 4C and Figure S3C).…”

“…Consistent with siRNA-mediated depletion of TFF3, AMPC inhibition of TFF3 in CMS4 CRC cells resulted in reduction of oncogenic behaviours: cell proliferation, cell survival, foci formation, 3D Matrigel growth, and reduced CSC-like behaviour. As mentioned, TFF3 has been reported to activate the HER family of receptor tyrosine kinases and its associated downstream pathways, including MAPK, AKT, and STAT3 [26]. We also demonstrated that inhibition of TFF3 by AMPC decreased ERK1/2 activation in a dose-dependent manner.…”

“…TFF3 is known to activate HER1/2 [26] and trigger the activation of multiple downstream signal transduction molecules, including the MAPKs, PI3K, COX-2, and STAT3 [15,30]. We performed western blot analysis to examine the phosphorylation of MAPKs, namely JNK, p38, and ERK1/2.…”

Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells

“…Next, we employed validated siRNA [ 34 ] to reduce expression of TFF3 in both CTE-Ishikawa and VE-Ishikawa cells when cultured in FM or CSF-PRFM. siRNA -mediated depletion of TFF3 protein in both CTE-Ishikawa or VE-Ishikawa cells markedly decreased basal protein levels of TFF3 compared to their control cells (Figure 6A ).…”