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Heat-Shock Transcription Factor HSF1 Has a Critical Role in Human Epidermal Growth Factor Receptor-2-Induced Cellular Transformation and Tumorigenesis

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Heat-Shock Transcription Factor HSF1 Has a Critical Role in Human Epidermal Growth Factor Receptor-2-Induced Cellular Transformation and Tumorigenesis Oncogene (2010) 29, 5204–5213 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis L Meng, VL Gabai and MY Sherman Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA The heat-shock transcription factor HSF1 was recently Introduction shown to have a key role in the development of tumors associated with activation of Ras or inactivation of p53. Induction of heat-shock protein (Hsp)72, Hsp27 and Here, we show that HSF1 is required for the cell other Hsps represents a highly conserved protective transformation and tumorigenesis induced by the human mechanism against environmental insults, which is epidermal growth factor receptor-2 (HER2) oncogene predominantly regulated by the heat-shock transcription responsible for aggressive breast tumors. Upon expression factor HSF1 (Lindquist and Craig, 1988; Sorger, 1991; of HER2, untransformed human mammary epithelial Morimoto et al., 1992). Recent reports showed that MCF-10A cells underwent neoplastic transformation, HSF1 has an essential role in the development of formed foci in culture and tumors in nude mouse lymphomas in p53-deficient mice and of carcinomas in xenografts. However, expression of HER2 in MCF-10A Ras tumor model (Dai et al., 2007; Min et al., 2007). cells with knockdown of HSF1 did not cause either foci Moreover, HSF1 was shown to support proliferation of formation or tumor growth in xenografts. The antitumori- several cancer cell lines (Dai et al., 2007), but specific genic effect of downregulation of HSF1 was associated mechanisms of these effects have not been explored. with HER2-induced accumulation of the cyclin-dependent Normal tissues or non-transformed cells usually kinase inhibitor p21 and decrease in the mitotic regulator express relatively low levels of Hsp72 and Hsp27, and survivin, which resulted in growth inhibition and cell these proteins are strongly upregulated following stress- senescence. In fact, either knockout of p21 or over- ful treatments in an HSF1-dependent manner (Jolly and expression of survivin alleviated these effects of HSF1 Morimoto, 2000). On the other hand, many human knockdown. The proliferation of certain human HER2- tumors and cancer cell lines express Hsp72 or/and positive breast cancer lines also requires HSF1, as its Hsp27 at elevated levels constitutively (Jaattela, 1999; knockdown led to upregulation of p21 and/or decrease in Jolly and Morimoto, 2000; Mosser and Morimoto, survivin, precipitating growth arrest. Similar effects were 2004; Calderwood et al., 2006). High levels of Hsp72 observed with a small-molecular-weight inhibitor of the and Hsp27 correlate with metastasis, resistance to heat-shock response NZ28. The effects of HSF1 knock- anticancer drugs and poor prognosis in many human down on the growth arrest and senescence of HER2- cancers (Ciocca and Calderwood, 2005). Previous results expressing cells were associated with downregulation of from this laboratory indicated that certain cancer cells heat-shock protein (Hsp)72 and Hsp27. Therefore, HSF1 become ‘addicted’ to high levels of Hsp72, as specific is critical for proliferation of HER2-expressing cells, most depletion of Hsp72 rapidly suppressed cell proliferation likely because it maintains the levels of HSPs, which in and precipitated senescence in several cancer lines, but not turn control regulators of senescence p21 and survivin. in untransformed epithelial cells (Yaglom et al.,2007; Oncogene (2010) 29, 5204–5213; doi:10.1038/onc.2010.277; Gabai et al., 2009). Interestingly, in different cancer cells published online 12 July 2010 distinct senescence signaling pathways were activated upon depletion of Hsp72, depending on the presence of Keywords: HSF1; HER2; growth arrest; senescence; either phosphatidylinositol 3-kinase, catalytic, alpha p21; survivin polypeptide or Ras oncogenes (Gabai et al., 2009). Constitutively elevated expression of Hsp72 and/or Hsp27 in cancers is often due to the HSF1-dependent mechanisms (although sometimes it is HSF1-indepen- dent) (Cai and Zhu, 2003; Wu et al., 2005). However, the role of HSF1 in cancers may not be limited to regulating the expression of HSPs, as this transcription factor also Correspondence: Dr MY Sherman or Dr VL Gabai, Department of controls expression of many other proteins (Cahill et al., Biochemistry, Boston University School of Medicine, 72 East Concord 1996, 1997; Singh et al., 2000, 2002; Xie et al., 2002a, b). Street K-323, Boston, MA 02118, USA. E-mails: [email protected] or [email protected] Human epidermal growth factor receptor-2 (HER2) is Received 13 August 2009; revised 25 May 2010; accepted 9 June 2010; a member of the epidermal growth factor receptor published online 12 July 2010 tyrosine kinase family, which is overexpressed in HSF1 is essential for HER2-induced transformation L Meng et al 5205 25–30% of human breast and ovarian cancers (Moasser, led to merely mild upregulation of vimentin, and foci 2007). Besides activating mitogenic pathways, HER2 formation was inhibited (Figure 1b and c), indicating can upregulate growth-inhibitory/senescence signaling that HSF1 is required for HER2-induced transforma- (Trost et al., 2005), suggesting that malignant transfor- tion in vitro. Of note, in contrast to late-passage cells, mation needs not only oncogene activation but also a infection with HER2-expressing retrovirus of early- shutdown of senescence pathways. Here, in addressing passage MCF-10A cells did not cause transformation the role of HSF1 in HER2-induced tumorigenesis, we and triggered senescence even without HSF1 depletion discovered that HSF1 controls senescence signaling (not shown). initiated by HER2. If infection with shHSF1 retrovirus followed infection with HER2 retrovirus, downregulation of HSF1 still triggered senescence even in fully transformed MCF- Results 10A cells (Supplementary Figure S1), indicating that HSF1 is necessary for the maintenance of growth of Depletion of HSF1 inhibits the transformation ability HER2-transformed cells. of HER2 To address the role of HSF1 in tumorigenesis in vivo, To investigate the role of HSF1 in neoplastic transfor- HER2-expressing control and shHSF1 cells were tested mation, we depleted HSF1 from breast epithelial MCF- for their ability to form tumors in xenografts. Control 10A cells, and then introduced the HER2 oncogene. HER2-expressing cells formed noticeable tumors at Briefly, late-passage MCF-10A cells were infected with the injection site by day 3 post-injection (Figure 1d). control retrovirus or retrovirus expressing the small However, HER2-expressing cells depleted of HSF1 hairpin RNA (shRNA) against HSF1 (shHSF1), fol- could not form tumors at least until day 25. Two lowed by puromycin selection, which resulted in more tumors appeared at days 26 and 35 post-injection, and than 95% depletion of HSF1 (Figure 1a). These these tumors were much smaller. Importantly, in both treatments did not affect cell viability, and only slightly tumors control of HSF1 expression by shRNA was lost, diminished growth (see below in Figure 2a), further and levels of HSF1 partially restored (Supplementary indicating that HSF1 is dispensable for growth of Figure S2), further supporting that in the absence of untransformed cells. Then, cells were infected with HSF1, HER2-induced tumors cannot be formed. retrovirus expressing the constitutively active HER2 mutant V664E, which led to increased expression of HER2 triggers growth arrest and senescence in cells with vimentin and formation of foci (Figures 1b and c), knockdown of HSF1 indicating that cells underwent neoplastic transforma- We investigated the effects of HSF1 on the growth rates tion. In contrast, expression of HER2 in shHSF1 cells of HER2-expressing cells. Control and shHSF1 cells Cont. shHSF1 Cont. shHSF1 EV HER2EV HER2 HSF1 vimentin β-actin β-actin Cont. EV shHSF1 EV 1000 Cont.-1 Cont.-2 900 Cont.-3 Cont.-4 ) 800 3 shHSF1-1 700 shHSF1-2 600 shHSF1-3 shHSF1-4 500 Cont. HER2 shHSF1 HER2 400 300 Tumor volume (mm volume Tumor 200 100 0 0 5 10 15 20 25 30 35 Days after injection Figure 1 Human epidermal growth factor receptor-2 (HER2)-induced MCF-10A transformation requires HSF1. (a) HSF1 depletion by small hairpin RNA against HSF1 (shHSF1) virus. MCF-10A cells were infected with control (Cont.) or shHSF1 retroviruses, and following 3 days of selection, HSF1 levels were measured by immunoblotting. (b) Effect of HSF1 depletion on the HER2-induced vimentin expression. Control (Cont. and shHSF1 MCF-10A cells were infected with control empty vector (EV) or HER2- overexpressing (HER2) retroviruses, and vimentin levels were measured on day 4 post-infection. (c) Effect of HSF1 depletion on the HER2-induced foci formation. Cells described in b) were stained with hematoxylin to visualize the foci. Dark masses in the bottom left panel represent the foci. (d) HSF1 depletion suppresses tumor emergence in xenografts. Growth curves of individual tumor in xenografts of HER2-expressing Cont. and shHSF1 MCF-10A cells. Oncogene HSF1 is essential for HER2-induced transformation L Meng et al 5206 1000000 Cont. EV Cont. EV shHSF1 EV Cont. HER2 shHSF1 EV shHSF1 HER2 100000 10000 Cont. HER2 shHSF1 HER2 Cell number per well Cell number 1000 2468 Days after infection Cont. EV shHSF1 EV ** 80 70 60 50 40 Cont. HER2 shHSF1 HER2 cells -gal-positive 30 β 20 % of 10 0 Cont. EV Cont. HER2shHSF1 EV shHSF1 HER2 Figure 2 Human epidermal growth factor receptor-2 (HER2) triggers senescence in HSF1-deficient MCF-10A cells. (a) Growth curves of control (Cont.) and small hairpin RNA against HSF1 (shHSF1) MCF-10A cells with (HER2) or without (empty vector, EV) HER2 overexpression. (b) Representative morphology of MCF-10A cultures described in (a). Please note that the mass seen in the bottom left panel represents the focus. (c) b-galactosidase (b-gal) activity staining of MCF-10A populations described in (a) and its quantification. were infected with HER2-expressing retrovirus or p21 is a mediator in HER2-induced senescence upon control retrovirus.
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