Abstract
Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3-kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.
Highlights
Activated kinase signaling stimulates autophosphorylation, which in turn promotes downstream signaling through the phosphoinositide-3-kinase (PI3K)–AKT and Ras–Raf–MEK– ERK1/2
Our results show for the first time that human epidermal growth factor receptor-2 (HER2)/ErbB2 overexpression controls heat-shock factor 1 (HSF1) activity, with subsequent stabilization of numerous tumor-promoting heat-shock protein 90 (HSP90) clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer
As we recently identified MIF as a new heat-shock protein 90 (HSP90) chaperone client,[7] we asked whether HER2mediated MIF regulation is controlled by the HSP90 chaperone machinery
Summary
Activated kinase signaling stimulates autophosphorylation, which in turn promotes downstream signaling through the phosphoinositide-3-kinase (PI3K)–AKT and Ras–Raf–MEK– ERK1/2 The link between MIF and HER2 we found earlier[7] led us to the question whether elevated MIF levels might be linked to and perhaps causally dependent on the molecular subtype of HER2-postive breast cancers. In line with this notion, correlation studies found elevated MIF levels in HER2-positive human breast cancers.[33] To test whether HER2 signaling directly regulates MIF levels, we chose in the current study a set of HER2-overexpressing human breast cancer cell lines and treated them pharmacologically with HER2 inhibitors. As we recently identified MIF as a new heat-shock protein 90 (HSP90) chaperone client,[7] we asked whether HER2mediated MIF regulation is controlled by the HSP90 chaperone machinery
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