HER2/EGFR-AKT Signaling Switches TGFβ from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer

Cancer Research
Fei HuangYe-Guang Chen

Abstract

TGFβ signaling inhibits cell proliferation to block cancer initiation, yet it also enhances metastasis to promote malignancy during breast cancer development. The mechanisms underlying these differential effects are still unclear. Here, we report that HER2/EGFR signaling switches TGFβ function in breast cancer cells from antiproliferation to cancer promotion. Inhibition of HER2/EGFR activity attenuated TGFβ-induced epithelial-mesenchymal transition and migration but enhanced the antiproliferative activity of TGFβ. Activation of HER2/EGFR induced phosphorylation of Smad3 at Ser208 of the linker region through AKT, which promoted the nuclear accumulation of Smad3 and subsequent expression of the genes related to EMT and cell migration. In contrast, HER2/EGFR signaling had no effects on the nuclear localization of Smad2. Knockdown of Smad3, but not Smad2, blocked TGFβ-induced breast cancer cell migration. We observed a positive correlation between the nuclear localization of Smad3 and HER2 activation in advanced human breast cancers. Our results demonstrate a key role for HER2/EGFR in differential regulation of Smad3 activity to shift TGFβ function from antitumorigenic to protumorigenic during breast cancer development.Significanc...Continue Reading

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Citations

Mar 23, 2019·Oncotarget·Qiaoni Shi, Ye-Guang Chen
Dec 12, 2018·Journal of Cellular Physiology·Amirhossein AhmadiKeywan Mortezaee
Jun 13, 2020·Frontiers in Cellular Neuroscience·Jianhua ZhouJinghui Huang
Mar 23, 2021·Bulletin du cancer·Nejla FouratiJamel Daoud
Jul 29, 2021·Endocrinology·Aloran MazumderSvasti Haricharan
Sep 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Hanqiang DengMartin A Schwartz
Sep 12, 2020·Recent Patents on Anti-cancer Drug Discovery·Arunaksharan Narayanankutty
Sep 26, 2021·Cancer Cell International·Wanqiong YuanZhongjun Liu
Jul 10, 2020·Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology·Yousif A KaririEmad A Rakha

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