PMID- 24384723 OWN - NLM STAT- MEDLINE DCOM- 20140902 LR - 20220311 IS - 2041-4889 (Electronic) VI - 5 IP - 1 DP - 2014 Jan 2 TI - HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. PG - e980 LID - 10.1038/cddis.2013.508 [doi] AB - 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. FAU - Schulz, R AU - Schulz R AD - Institute of Molecular Oncology, GZMB, University of Gottingen, Gottingen 37077, Germany. FAU - Streller, F AU - Streller F AD - Institute of Molecular Oncology, GZMB, University of Gottingen, Gottingen 37077, Germany. FAU - Scheel, A H AU - Scheel AH AD - Institute for Pathology Nordhessen, Kassel 34119, Germany. FAU - Ruschoff, J AU - Ruschoff J AD - Institute for Pathology Nordhessen, Kassel 34119, Germany. FAU - Reinert, M-C AU - Reinert MC AD - Institute of Molecular Oncology, GZMB, University of Gottingen, Gottingen 37077, Germany. FAU - Dobbelstein, M AU - Dobbelstein M AD - Institute of Molecular Oncology, GZMB, University of Gottingen, Gottingen 37077, Germany. FAU - Marchenko, N D AU - Marchenko ND AD - Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Moll, U M AU - Moll UM AD - 1] Institute of Molecular Oncology, GZMB, University of Gottingen, Gottingen 37077, Germany [2] Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. LA - eng GR - R01 CA176647/CA/NCI NIH HHS/United States GR - R01CA176647/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140102 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (DNA-Binding Proteins) RN - 0 (HSF1 protein, human) RN - 0 (HSP90 Heat-Shock Proteins) RN - 0 (Heat Shock Transcription Factors) RN - 0 (Macrophage Migration-Inhibitory Factors) RN - 0 (Transcription Factors) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.2.1 (MIF protein, human) SB - IM MH - Animals MH - Breast Neoplasms/genetics/*metabolism MH - Cell Line, Tumor MH - DNA-Binding Proteins/genetics/*metabolism MH - Female MH - HSP90 Heat-Shock Proteins/genetics/*metabolism MH - Heat Shock Transcription Factors MH - Humans MH - Intramolecular Oxidoreductases/genetics/*metabolism MH - Macrophage Migration-Inhibitory Factors/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Phosphatidylinositol 3-Kinases/genetics/metabolism MH - Receptor, ErbB-2/genetics/*metabolism MH - Transcription Factors/genetics/*metabolism PMC - PMC4040658 EDAT- 2014/01/05 06:00 MHDA- 2014/09/03 06:00 PMCR- 2014/01/01 CRDT- 2014/01/04 06:00 PHST- 2013/07/16 00:00 [received] PHST- 2013/10/30 00:00 [revised] PHST- 2013/11/11 00:00 [accepted] PHST- 2014/01/04 06:00 [entrez] PHST- 2014/01/05 06:00 [pubmed] PHST- 2014/09/03 06:00 [medline] PHST- 2014/01/01 00:00 [pmc-release] AID - cddis2013508 [pii] AID - 10.1038/cddis.2013.508 [doi] PST - epublish SO - Cell Death Dis. 2014 Jan 2;5(1):e980. doi: 10.1038/cddis.2013.508.