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

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. TGFβ signaling can shift from inhibiting to promoting breast cancer development via HER2/EGFR AKT-mediated phosphorylation of Smad3 at S208, enhancing its nuclear accumulation and upregulation of EMT-related genes. http://cancerres.aacrjournals.org/content/canres/78/21/6073/F1.large.jpg .

Expression of Podoplanin in Mammary Cancers in Female Dogs

“…HER2 is an important marker used in the diagnosis of breast cancer in women, while it is more and more frequently used for IHC tests in veterinary medicine (9)(10)(11). This receptor participates in the oncogenesis processes, by affecting cancer cell migration, increasing angiogenesis, and metastasis of cancer cells (9)(10)(11)44). In these published studies, there is no relationship reported between the intensity of the HER2 receptor expression and the level of PDPN expression in CAFs in mammary tumours in bitches.…”

HER4 promotes the progression of colorectal cancer by promoting epithelial‑mesenchymal transition

“…These discrepancies can be explained by differences in the mouse model experiment of methodology, mouse model age, antibodies and subject ethnicity in the studies (21). expression of Her1 is known to be closely associated with Her2 expression (24)(25)(26)(27). in breast cancer, Smad3, which can convert transforming growth factor-β into a carcinogenic factor, is activated when Her1 and Her2 are co-expressed, resulting in tumor progression (24).…”

“…expression of Her1 is known to be closely associated with Her2 expression (24)(25)(26)(27). in breast cancer, Smad3, which can convert transforming growth factor-β into a carcinogenic factor, is activated when Her1 and Her2 are co-expressed, resulting in tumor progression (24). The functional tyrosine domain of Her2 activates Her3 or Her1, promoting tumor development via activation of signaling pathways such as STaT3, raS-mitogen-activated protein kinase and Pi3K (25)(26)(27).…”

“…The functional tyrosine domain of Her2 activates Her3 or Her1, promoting tumor development via activation of signaling pathways such as STaT3, raS-mitogen-activated protein kinase and Pi3K (25)(26)(27). Previous studies showed that the expression of Her1, Her2 and Her3 exhibits complex interactions (24)(25)(26)(27). The present results suggested that Her4 had no significant association with HER1, HER2 or HER3 in the tissue collected from patients with crc.…”

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“…Our study elicits several unsolved issues that need further investigation. Firstly, as the crucial cytoplasmic signal transducers of TGF-β signaling, Smad2 and Smad3 have been indicated to exert different physiologic functions in different circumstances [1,[6][7][8]. Smad2 seems to have essential functions to mediate Activin/ Nodal signaling during embryogenesis, while Smad3 mediates TGF-β responses in adult tissues, such as growth inhibition, fibrotic responses in response to injury, synthesis of extracellular matrix proteins, immune suppression, EMT and cell migration [1,7,8].…”