Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells

L. Castiello, P. Sestili, G. Schiavoni, R. Dattilo, D.M. Monque, F. Ciaffoni, M. Iezzi, A. Lamolinara, A. Sistigu, F. Moschella, A.M. Pacca, D. Macchia, M. Ferrantini, A. Zeuner, M. Biffoni, E. Proietti, F. Belardelli, E. Aricò

Research output: Contribution to journalArticle

Abstract

Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neumice (neuT mice), IFNAR1/ neumice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuTmmospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDHlls, suggesting that IFN-I controls stemness in tumor cells.Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. © 2018 AACR.
Original languageEnglish
Pages (from-to)658-670
Number of pages13
JournalCancer immunology research
Volume6
Issue number6
DOIs
Publication statusPublished - 2018

Fingerprint

Neoplastic Stem Cells
Breast Neoplasms
Neoplasms
Transgenic Mice
Aldehyde Dehydrogenase
Carcinogenesis
Cytokines
Interferon Type I
Oncogenes
Antiviral Agents
Cell Line
Mutation
Antibodies
Growth

Keywords

  • aldehyde dehydrogenase 1a1
  • aldehyde dehydrogenase isoenzyme 1
  • epidermal growth factor receptor 2
  • interferon
  • unclassified drug
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • breast cancer
  • cancer cell
  • cancer growth
  • cancer patient
  • cancer prognosis
  • cancer stem cell
  • clonogenic assay
  • comparative study
  • enzyme activity
  • female
  • human
  • immunocompetent cell
  • immunohistochemistry
  • immunomodulation
  • immunophenotyping
  • in vitro study
  • in vivo study
  • male
  • mouse
  • nonhuman
  • oncogene neu
  • promoter region
  • RNA hybridization
  • RNA isolation

Cite this

Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells. / Castiello, L.; Sestili, P.; Schiavoni, G.; Dattilo, R.; Monque, D.M.; Ciaffoni, F.; Iezzi, M.; Lamolinara, A.; Sistigu, A.; Moschella, F.; Pacca, A.M.; Macchia, D.; Ferrantini, M.; Zeuner, A.; Biffoni, M.; Proietti, E.; Belardelli, F.; Aricò, E.

In: Cancer immunology research, Vol. 6, No. 6, 2018, p. 658-670.

Research output: Contribution to journalArticle

@article{05778e83329e454daba475a62d537312,
title = "Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells",
abstract = "Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neumice (neuT mice), IFNAR1/ neumice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuTmmospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDHlls, suggesting that IFN-I controls stemness in tumor cells.Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. {\circledC} 2018 AACR.",
keywords = "aldehyde dehydrogenase 1a1, aldehyde dehydrogenase isoenzyme 1, epidermal growth factor receptor 2, interferon, unclassified drug, animal experiment, animal model, animal tissue, Article, breast cancer, cancer cell, cancer growth, cancer patient, cancer prognosis, cancer stem cell, clonogenic assay, comparative study, enzyme activity, female, human, immunocompetent cell, immunohistochemistry, immunomodulation, immunophenotyping, in vitro study, in vivo study, male, mouse, nonhuman, oncogene neu, promoter region, RNA hybridization, RNA isolation",
author = "L. Castiello and P. Sestili and G. Schiavoni and R. Dattilo and D.M. Monque and F. Ciaffoni and M. Iezzi and A. Lamolinara and A. Sistigu and F. Moschella and A.M. Pacca and D. Macchia and M. Ferrantini and A. Zeuner and M. Biffoni and E. Proietti and F. Belardelli and E. Aric{\`o}",
note = "Cited By :2 Export Date: 11 April 2019 Correspondence Address: Belardelli, F.; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit{\`a}Italy; email: filippo.belardelli@iss.it Chemicals/CAS: epidermal growth factor receptor 2, 137632-09-8 Funding details: IG16891, IG 14297 Funding text 1: The research was supported in part by grants from the Italian Association for Research against Cancer (AIRC IG16891 and IG 14297). We thank M. Venditti and M. Spada for assistance with preliminary experiments on mice. We are grateful to Paola Di Matteo for kindly providing us the mammosphere medium and to Dr. Marta Baiocchi for scientific advice on NSG mice experiments. References: Vilcek, J., Fifty years of interferon research: Aiming at a moving target (2006) Immunity, 25, pp. 343-348; Rizza, P., Moretti, F., Capone, I., Belardelli, F., Role of type i interferon in inducing a protective immune response: Perspectives for clinical applications (2015) Cytokine Growth Factor Rev, 26, pp. 195-201; Gresser, I., Belardelli Fmaurycmaunoury, M.T., Injection ofmice with antibody to interferon enhances the growth of transplantable murine tumors (1983) J Exp Med, 158, pp. 2095-2107; Dunn, G.P., Bruce, A.T., Kcf, S., Shankaran, V., Uppaluri, R., Bui, J.D., A critical function for type i interferons in cancer immunoediting (2005) Nat Immunol, 6, pp. 722-729; Fuertes, M.B., Woo, S.-R., Burnett, B., Fu, Y.-X., Gajewski, T.F., Type i interferon response and innate immune sensing of cancer (2013) Trends Immunol, 34, pp. 67-73; Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A., McGuire, W.L., Human breast cancer: Correlation of relapse and survival with amplification of the her-2/neu oncogene (1987) Science, 235, pp. 177-182; Perou, C.M., S{\o}rlie, T., Eisen, M.B., Van De Rijn, M., Jeffrey, S.S., Rees, C.A., Molecular portraits of human breast tumours (2000) Nature, 406, pp. 747-752; Lollini, P.-L., Cavallo, F., Nanni, P., Quaglino, E., The promise of preventive cancer vaccines (2015) Vaccines Multidisciplinary Digital Publishing Institute (MDPI, 3, pp. 467-489; Muller, W.J., Sinn, E., Pattengale, P.K., Wallace, R., Leder, P., Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene (1988) Cell, 54, pp. 105-115; Pannellini, T., Forni, G., Musiani, P., Immunobiology of her2/neu transgenic mice (2004) Breast Dis, 20, pp. 33-42; Arico, E., Sestili, P., Carpinelli, G., Canese, R., Cecchetti, S., Schiavoni, G., Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis (2016) Oncotarget, 7, pp. 59754-59765; Nanni, P., Nicoletti, G., De Giovanni, C., Landuzzi, L., Di Carlo, E., Cavallo, F., Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice (2001) J Exp Med, 194, pp. 1195-1205; Bartucci, M., Svensson, S., Romania, P., Dattilo, R., Patrizii, M., Signore, M., Therapeutic targeting of chk1 in NSCLC stem cells during chemotherapy (2012) Cell Death Differ, 19, pp. 768-778; Cappello, P., Triebel, F., Iezzi, M., Caorsi, C., Quaglino, E., Lollini, P.-L., LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in her-2/neu transgenic BALB/c mice (2003) Cancer Res, 63, pp. 2518-2525; Ross, D.T., Scherf, U., Eisen, M.B., Perou, C.M., Rees, C., Spellman, P., Systematic variation in gene expression patterns in human cancer cell lines (2000) Nat Genet, 24, pp. 227-235; Subramanian, A., Tamayo, P., Mootha Vkmukherjee, S., Blgillette Ma, E., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles (2005) Proc Natl Acad Sci USA, 102, pp. 15545-15550; Gyorffy, B., Lanczky, A., Eklund, A.C., Denkert, C., Budczies, J., Li, Q., An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients (2010) Breast Cancer Res Treat, 123, pp. 725-731; Muller, U., Steinhoff, U., Reis, L., Hemmi, S., Pavlovic, J., Zinkernagel, R., Functional role of type i and type II interferons in antiviral defense (1994) Science, 264, pp. 1918-1921; Hosseini, H., Mms, O., Hoffmann, M., Harper, K.L., Sosa, M.S., Werner-Klein, M., Early dissemination seedsmetastasis in breast cancer (2016) Nature, 540, pp. 552-558; Bielenberg, D., Donawho, C., Bucana, C.D., Fidler, I.J., Evidence for the causal role of endogenous interferon-a/b in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms (2002) Clin Exp Metastasis, 19, pp. 609-615; Yoshida, G.J., Metabolic reprogramming: The emerging concept and associated therapeutic strategies (2015) J Exp Clin Cancer Res, 34, p. 111; Sponziello, M., Rosignolo, F., Celano, M., Maggisano, V., Pecce, V., De Rose, R.F., Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells (2016) Mol Cell Endocrinol, 431, pp. 123-132; Kashima, H., Wu, R.-C., Wang, Y., Sinno, A.K., Miyamoto, T., Shiozawa, T., Laminin c1 expression by uterine carcinoma cells is associated with tumor progression (2015) Gynecol Oncol, 139, pp. 338-344; Charafe-Jauffret, E., Ginestier, C., Bertucci, F., Cabaud, O., Wicinski, J., Finetti, P., ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program (2013) Cancer Res, 73, pp. 7290-7300; Liu, Y., Lv, D., Duan, J., Xu, S., Zhang, J., Yang, X., ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: A systematic review and meta-analysis (2014) BMC Cancer, 14, p. 444; Korkaya, H., Paulson, A., Iovino, F., Wicha, M.S., HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion (2008) Oncogene, 27, pp. 6120-6130; Magnifico, A., Albano, L., Campaner, S., Delia, D., Castiglioni, F., Gasparini, P., Tumor-initiating cells of her2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab (2009) Clin Cancer Res, 15, pp. 2010-2021; Grange, C., Lanzardo, S., Cavallo, F., Camussi, G., Bussolati, B., Sca-1 identifies the tumor-initiating cells in mammary tumors of balb-neut transgenic mice (2008) Neoplasia, 10, pp. 1433-1443; Lo, P.-K., Kanojia, D., Liu, X., Singh, U.P., Berger, F.G., Wang, Q., CD49f and cd61 identify her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFb signaling (2012) Oncogene, 31, pp. 2614-2626; Liu, J.C., Egan, S.E., Zacksenhaus, E., ATumor initiating cell-enriched prognostic signature for her2ra breast cancer; Rationale, new features, controversies and future directions (2013) Oncotarget, 4, pp. 1317-1328; Nguyen, L.V., Vanner, R., Dirks, P., Eaves, C.J., Cancer stem cells: An evolving concept (2012) Nat Rev Cancer, 12, p. 133; Gresser, I., Tovey, M.G., Bandu, M.E., Maury, C., Brouty-Boye, D., Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum i. Rapid evolution of encephalomyocarditis virus infection (1976) J Exp Med, 144, pp. 1305-1315; Belardelli, F., Vignaux, F., Proietti, E., Gresser, I., Injection ofmice with antibody to interferon renders peritoneal macrophages permissive for vesicular stomatitis virus and encephalomyocarditis virus (1984) Proc Natl Acad Sci USA, 81, pp. 602-606; Gresser, I., Vignaux, F., Belardelli, F., Tovey, M.G., Maunoury, M.T., Injection of mice with antibody to mouse interferon alpha/beta decreases the level of 20-50 oligoadenylate synthetase in peritoneal macrophages (1985) J Virol, 53, pp. 221-227; Celia-Terrassa, T., Liu, D.D., Choudhury, A., Hang, X., Wei, Y., Zamalloa, J., Normal and cancerous mammary stem cells evade interferon-induced constraint through the mir-199a-lcor axis (2017) Nat Cell Biol, 19, pp. 711-723; Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D.P., Adam, J., Cancer cell-autonomous contribution of type i interferon signaling to the efficacy of chemotherapy (2014) Nat Med, 20, pp. 1301-1309; Ferrantini, M., Capone, I., Belardelli, F., Interferon-alpha and cancer:mechanisms of action and new perspectives of clinical use (2007) Biochimie, 89, pp. 884-893; Dunn, G.P., Koebel, C.M., Schreiber, R.D., Interferons, immunity and cancer immunoediting (2006) Nat Rev Immunol, 6, pp. 836-848; Rolla, S., Nicolo, S., Forni, G., Cavallo, F., Distinct and non-overlapping t cell receptor repertoires expanded by DNA vaccination in wild-type and HER-2 transgenic BALB/c mice (2006) J Immunol, 177, pp. 7626-7633; Cousens, L.P., Peterson, R., Hsu, S., Dorner, A., Altman, J.D., Ahmed, R., Two roads diverged: Interferon alpha/beta- and interleukin 12-mediated pathways in promoting t cell interferon gamma responses during viral infection (1999) J Exp Med, 189, pp. 1315-1328; Moasser, M.M., The oncogene her2: Its signaling and transforming functions and its role in human cancer pathogenesis (2007) Oncogene, 26, pp. 6469-6487; Rodriguez-Torres, M., Allan, A.L., Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors (2016) Clin Exp Metastasis, 33, pp. 97-113; Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome (2007) Cell Stem Cell, 1, pp. 555-567; Korkaya, H., Liu, S., Wicha, M.S., Breast cancer stem cells, cytokine networks, and the tumor microenvironment (2011) J Clin Invest, 121, pp. 3804-3809; Buoncervello, M., Romagnoli, G., Buccarelli, M., Fragale, A., Toschi, E., Parlato, S., IFN-a potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer (2016) Oncotarget, 7, pp. 26361-26373; Qadir, A.S., Ceppi, P., Brockway, S., Weichselbaum, R.R., Yu, J., Peter, M.E., CD95/fas increases stemness in cancer cells by inducing a stat1-dependent type i interferon response (2017) Cell Rep, 18, pp. 2373-2386; Dean, M., Fojo, T., Bates, S., Tumour stem cells and drug resistance (2005) Nat Rev Cancer, 5, pp. 275-284; Creighton, C.J., Li, X., Landis, M., Dixon, J.M., Neumeister, V.M., Sjolund, A., Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features (2009) Proc Natl Acad Sci USA, 106, pp. 13820-13825; Khoury, T., Ademuyiwa, F.O., Chandraseekhar, R., Jabbour, M., DeLeo, A., Ferrone, S., Aldehyde dehydrogenase 1a1 expression in breast cancer is associated with stage, triple negativity, and outcome to neoadjuvant chemotherapy (2012) Mod Pathol, 25, pp. 388-397; Tomita, H., Tanaka, K., Tanaka, T., Hara, A., Aldehyde dehydrogenase 1a1 in stem cells and cancer (2016) Oncotarget, 7, pp. 11018-11032; Stagg, J., Loi, S., Divisekera, U., Ngiow, S.F., Duret, H., Yagita, H., Anti-ERBB-2 mab therapy requires type i and II interferons and synergizes with anti-pd-1 or anti-cd137 mab therapy (2011) Proc Natl Acad Sci USA, 108, pp. 7142-7147; Legrier, M.E., Bieche, I., Gaston, J., Beurdeley, A., Yvonnet, V., Deas, O., Activation of ifn/stat1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer (2016) Br J Cancer, 114, pp. 177-187; Talpaz, M., Hehlmann, R., Quintas-Cardama, A., Mercer, J., Cortes, J., Reemergence of interferon-a in the treatment of chronic myeloid leukemia (2013) Leukemia, 27, pp. 803-812",
year = "2018",
doi = "10.1158/2326-6066.CIR-17-0675",
language = "English",
volume = "6",
pages = "658--670",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells

AU - Castiello, L.

AU - Sestili, P.

AU - Schiavoni, G.

AU - Dattilo, R.

AU - Monque, D.M.

AU - Ciaffoni, F.

AU - Iezzi, M.

AU - Lamolinara, A.

AU - Sistigu, A.

AU - Moschella, F.

AU - Pacca, A.M.

AU - Macchia, D.

AU - Ferrantini, M.

AU - Zeuner, A.

AU - Biffoni, M.

AU - Proietti, E.

AU - Belardelli, F.

AU - Aricò, E.

N1 - Cited By :2 Export Date: 11 April 2019 Correspondence Address: Belardelli, F.; Department of Oncology and Molecular Medicine, Istituto Superiore di SanitàItaly; email: filippo.belardelli@iss.it Chemicals/CAS: epidermal growth factor receptor 2, 137632-09-8 Funding details: IG16891, IG 14297 Funding text 1: The research was supported in part by grants from the Italian Association for Research against Cancer (AIRC IG16891 and IG 14297). We thank M. Venditti and M. Spada for assistance with preliminary experiments on mice. We are grateful to Paola Di Matteo for kindly providing us the mammosphere medium and to Dr. Marta Baiocchi for scientific advice on NSG mice experiments. References: Vilcek, J., Fifty years of interferon research: Aiming at a moving target (2006) Immunity, 25, pp. 343-348; Rizza, P., Moretti, F., Capone, I., Belardelli, F., Role of type i interferon in inducing a protective immune response: Perspectives for clinical applications (2015) Cytokine Growth Factor Rev, 26, pp. 195-201; Gresser, I., Belardelli Fmaurycmaunoury, M.T., Injection ofmice with antibody to interferon enhances the growth of transplantable murine tumors (1983) J Exp Med, 158, pp. 2095-2107; Dunn, G.P., Bruce, A.T., Kcf, S., Shankaran, V., Uppaluri, R., Bui, J.D., A critical function for type i interferons in cancer immunoediting (2005) Nat Immunol, 6, pp. 722-729; Fuertes, M.B., Woo, S.-R., Burnett, B., Fu, Y.-X., Gajewski, T.F., Type i interferon response and innate immune sensing of cancer (2013) Trends Immunol, 34, pp. 67-73; Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A., McGuire, W.L., Human breast cancer: Correlation of relapse and survival with amplification of the her-2/neu oncogene (1987) Science, 235, pp. 177-182; Perou, C.M., Sørlie, T., Eisen, M.B., Van De Rijn, M., Jeffrey, S.S., Rees, C.A., Molecular portraits of human breast tumours (2000) Nature, 406, pp. 747-752; Lollini, P.-L., Cavallo, F., Nanni, P., Quaglino, E., The promise of preventive cancer vaccines (2015) Vaccines Multidisciplinary Digital Publishing Institute (MDPI, 3, pp. 467-489; Muller, W.J., Sinn, E., Pattengale, P.K., Wallace, R., Leder, P., Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene (1988) Cell, 54, pp. 105-115; Pannellini, T., Forni, G., Musiani, P., Immunobiology of her2/neu transgenic mice (2004) Breast Dis, 20, pp. 33-42; Arico, E., Sestili, P., Carpinelli, G., Canese, R., Cecchetti, S., Schiavoni, G., Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis (2016) Oncotarget, 7, pp. 59754-59765; Nanni, P., Nicoletti, G., De Giovanni, C., Landuzzi, L., Di Carlo, E., Cavallo, F., Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice (2001) J Exp Med, 194, pp. 1195-1205; Bartucci, M., Svensson, S., Romania, P., Dattilo, R., Patrizii, M., Signore, M., Therapeutic targeting of chk1 in NSCLC stem cells during chemotherapy (2012) Cell Death Differ, 19, pp. 768-778; Cappello, P., Triebel, F., Iezzi, M., Caorsi, C., Quaglino, E., Lollini, P.-L., LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in her-2/neu transgenic BALB/c mice (2003) Cancer Res, 63, pp. 2518-2525; Ross, D.T., Scherf, U., Eisen, M.B., Perou, C.M., Rees, C., Spellman, P., Systematic variation in gene expression patterns in human cancer cell lines (2000) Nat Genet, 24, pp. 227-235; Subramanian, A., Tamayo, P., Mootha Vkmukherjee, S., Blgillette Ma, E., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles (2005) Proc Natl Acad Sci USA, 102, pp. 15545-15550; Gyorffy, B., Lanczky, A., Eklund, A.C., Denkert, C., Budczies, J., Li, Q., An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients (2010) Breast Cancer Res Treat, 123, pp. 725-731; Muller, U., Steinhoff, U., Reis, L., Hemmi, S., Pavlovic, J., Zinkernagel, R., Functional role of type i and type II interferons in antiviral defense (1994) Science, 264, pp. 1918-1921; Hosseini, H., Mms, O., Hoffmann, M., Harper, K.L., Sosa, M.S., Werner-Klein, M., Early dissemination seedsmetastasis in breast cancer (2016) Nature, 540, pp. 552-558; Bielenberg, D., Donawho, C., Bucana, C.D., Fidler, I.J., Evidence for the causal role of endogenous interferon-a/b in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms (2002) Clin Exp Metastasis, 19, pp. 609-615; Yoshida, G.J., Metabolic reprogramming: The emerging concept and associated therapeutic strategies (2015) J Exp Clin Cancer Res, 34, p. 111; Sponziello, M., Rosignolo, F., Celano, M., Maggisano, V., Pecce, V., De Rose, R.F., Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells (2016) Mol Cell Endocrinol, 431, pp. 123-132; Kashima, H., Wu, R.-C., Wang, Y., Sinno, A.K., Miyamoto, T., Shiozawa, T., Laminin c1 expression by uterine carcinoma cells is associated with tumor progression (2015) Gynecol Oncol, 139, pp. 338-344; Charafe-Jauffret, E., Ginestier, C., Bertucci, F., Cabaud, O., Wicinski, J., Finetti, P., ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program (2013) Cancer Res, 73, pp. 7290-7300; Liu, Y., Lv, D., Duan, J., Xu, S., Zhang, J., Yang, X., ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: A systematic review and meta-analysis (2014) BMC Cancer, 14, p. 444; Korkaya, H., Paulson, A., Iovino, F., Wicha, M.S., HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion (2008) Oncogene, 27, pp. 6120-6130; Magnifico, A., Albano, L., Campaner, S., Delia, D., Castiglioni, F., Gasparini, P., Tumor-initiating cells of her2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab (2009) Clin Cancer Res, 15, pp. 2010-2021; Grange, C., Lanzardo, S., Cavallo, F., Camussi, G., Bussolati, B., Sca-1 identifies the tumor-initiating cells in mammary tumors of balb-neut transgenic mice (2008) Neoplasia, 10, pp. 1433-1443; Lo, P.-K., Kanojia, D., Liu, X., Singh, U.P., Berger, F.G., Wang, Q., CD49f and cd61 identify her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFb signaling (2012) Oncogene, 31, pp. 2614-2626; Liu, J.C., Egan, S.E., Zacksenhaus, E., ATumor initiating cell-enriched prognostic signature for her2ra breast cancer; Rationale, new features, controversies and future directions (2013) Oncotarget, 4, pp. 1317-1328; Nguyen, L.V., Vanner, R., Dirks, P., Eaves, C.J., Cancer stem cells: An evolving concept (2012) Nat Rev Cancer, 12, p. 133; Gresser, I., Tovey, M.G., Bandu, M.E., Maury, C., Brouty-Boye, D., Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum i. Rapid evolution of encephalomyocarditis virus infection (1976) J Exp Med, 144, pp. 1305-1315; Belardelli, F., Vignaux, F., Proietti, E., Gresser, I., Injection ofmice with antibody to interferon renders peritoneal macrophages permissive for vesicular stomatitis virus and encephalomyocarditis virus (1984) Proc Natl Acad Sci USA, 81, pp. 602-606; Gresser, I., Vignaux, F., Belardelli, F., Tovey, M.G., Maunoury, M.T., Injection of mice with antibody to mouse interferon alpha/beta decreases the level of 20-50 oligoadenylate synthetase in peritoneal macrophages (1985) J Virol, 53, pp. 221-227; Celia-Terrassa, T., Liu, D.D., Choudhury, A., Hang, X., Wei, Y., Zamalloa, J., Normal and cancerous mammary stem cells evade interferon-induced constraint through the mir-199a-lcor axis (2017) Nat Cell Biol, 19, pp. 711-723; Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D.P., Adam, J., Cancer cell-autonomous contribution of type i interferon signaling to the efficacy of chemotherapy (2014) Nat Med, 20, pp. 1301-1309; Ferrantini, M., Capone, I., Belardelli, F., Interferon-alpha and cancer:mechanisms of action and new perspectives of clinical use (2007) Biochimie, 89, pp. 884-893; Dunn, G.P., Koebel, C.M., Schreiber, R.D., Interferons, immunity and cancer immunoediting (2006) Nat Rev Immunol, 6, pp. 836-848; Rolla, S., Nicolo, S., Forni, G., Cavallo, F., Distinct and non-overlapping t cell receptor repertoires expanded by DNA vaccination in wild-type and HER-2 transgenic BALB/c mice (2006) J Immunol, 177, pp. 7626-7633; Cousens, L.P., Peterson, R., Hsu, S., Dorner, A., Altman, J.D., Ahmed, R., Two roads diverged: Interferon alpha/beta- and interleukin 12-mediated pathways in promoting t cell interferon gamma responses during viral infection (1999) J Exp Med, 189, pp. 1315-1328; Moasser, M.M., The oncogene her2: Its signaling and transforming functions and its role in human cancer pathogenesis (2007) Oncogene, 26, pp. 6469-6487; Rodriguez-Torres, M., Allan, A.L., Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors (2016) Clin Exp Metastasis, 33, pp. 97-113; Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome (2007) Cell Stem Cell, 1, pp. 555-567; Korkaya, H., Liu, S., Wicha, M.S., Breast cancer stem cells, cytokine networks, and the tumor microenvironment (2011) J Clin Invest, 121, pp. 3804-3809; Buoncervello, M., Romagnoli, G., Buccarelli, M., Fragale, A., Toschi, E., Parlato, S., IFN-a potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer (2016) Oncotarget, 7, pp. 26361-26373; Qadir, A.S., Ceppi, P., Brockway, S., Weichselbaum, R.R., Yu, J., Peter, M.E., CD95/fas increases stemness in cancer cells by inducing a stat1-dependent type i interferon response (2017) Cell Rep, 18, pp. 2373-2386; Dean, M., Fojo, T., Bates, S., Tumour stem cells and drug resistance (2005) Nat Rev Cancer, 5, pp. 275-284; Creighton, C.J., Li, X., Landis, M., Dixon, J.M., Neumeister, V.M., Sjolund, A., Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features (2009) Proc Natl Acad Sci USA, 106, pp. 13820-13825; Khoury, T., Ademuyiwa, F.O., Chandraseekhar, R., Jabbour, M., DeLeo, A., Ferrone, S., Aldehyde dehydrogenase 1a1 expression in breast cancer is associated with stage, triple negativity, and outcome to neoadjuvant chemotherapy (2012) Mod Pathol, 25, pp. 388-397; Tomita, H., Tanaka, K., Tanaka, T., Hara, A., Aldehyde dehydrogenase 1a1 in stem cells and cancer (2016) Oncotarget, 7, pp. 11018-11032; Stagg, J., Loi, S., Divisekera, U., Ngiow, S.F., Duret, H., Yagita, H., Anti-ERBB-2 mab therapy requires type i and II interferons and synergizes with anti-pd-1 or anti-cd137 mab therapy (2011) Proc Natl Acad Sci USA, 108, pp. 7142-7147; Legrier, M.E., Bieche, I., Gaston, J., Beurdeley, A., Yvonnet, V., Deas, O., Activation of ifn/stat1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer (2016) Br J Cancer, 114, pp. 177-187; Talpaz, M., Hehlmann, R., Quintas-Cardama, A., Mercer, J., Cortes, J., Reemergence of interferon-a in the treatment of chronic myeloid leukemia (2013) Leukemia, 27, pp. 803-812

PY - 2018

Y1 - 2018

N2 - Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neumice (neuT mice), IFNAR1/ neumice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuTmmospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDHlls, suggesting that IFN-I controls stemness in tumor cells.Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. © 2018 AACR.

AB - Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neumice (neuT mice), IFNAR1/ neumice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuTmmospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDHlls, suggesting that IFN-I controls stemness in tumor cells.Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. © 2018 AACR.

KW - aldehyde dehydrogenase 1a1

KW - aldehyde dehydrogenase isoenzyme 1

KW - epidermal growth factor receptor 2

KW - interferon

KW - unclassified drug

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - breast cancer

KW - cancer cell

KW - cancer growth

KW - cancer patient

KW - cancer prognosis

KW - cancer stem cell

KW - clonogenic assay

KW - comparative study

KW - enzyme activity

KW - female

KW - human

KW - immunocompetent cell

KW - immunohistochemistry

KW - immunomodulation

KW - immunophenotyping

KW - in vitro study

KW - in vivo study

KW - male

KW - mouse

KW - nonhuman

KW - oncogene neu

KW - promoter region

KW - RNA hybridization

KW - RNA isolation

U2 - 10.1158/2326-6066.CIR-17-0675

DO - 10.1158/2326-6066.CIR-17-0675

M3 - Article

VL - 6

SP - 658

EP - 670

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 6

ER -