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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2017

01-11-2017 | Preclinical study

A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells

Authors: Yoko Chihara, Masafumi Shimoda, Ami Hori, Ako Ohara, Yasuto Naoi, Jun-ichiro Ikeda, Naofumi Kagara, Tomonori Tanei, Atsushi Shimomura, Kenzo Shimazu, Seung Jin Kim, Shinzaburo Noguchi

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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Abstract

Purpose

Resistance against anti-HER2 drugs in HER2-positive breast cancer is a major obstacle to the improving prognosis. Transforming growth factor β (TGFβ) is a cytokine involved in the acquisition of more malignant phenotypes through epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. The aim of this study was to investigate the effects of TGFβ and its downstream SMAD pathway on resistance to anti-HER2 drugs.

Methods

HER2-positive breast cancer cell lines were stimulated with TGFβ for 14 days. Then, the sensitivity to trastuzumab and lapatinib and the expression levels of various EMT and CSC markers were examined. The correlation of nuclear SMAD3 expression in untreated breast tumor tissues with trastuzumab efficacy in neoadjuvant settings was examined. The effect of a small-molecule inhibitor of SMAD3 (SIS3) on resistance to anti-HER2 drugs was explored.

Results

We found that continuous activation of the TGFβ-SMAD3 pathway induced resistance to anti-HER2 drugs and CSC traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFβ required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. SIS3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells.

Conclusions

This study indicates that the TGFβ-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs. Thus, SMAD3 is a potential therapeutic target that can inhibit resistance and restore sensitivity to anti-HER2 drugs.
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Metadata
Title
A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells
Authors
Yoko Chihara
Masafumi Shimoda
Ami Hori
Ako Ohara
Yasuto Naoi
Jun-ichiro Ikeda
Naofumi Kagara
Tomonori Tanei
Atsushi Shimomura
Kenzo Shimazu
Seung Jin Kim
Shinzaburo Noguchi
Publication date
01-11-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4382-6

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