Increasing CD44+/CD24- tumor stem cells, and upregulation of COX-2 and HDAC6, as major functions of HER2 in breast tumorigenesis

Molecular Cancer - 2010
Kai-Hung Wang1, An-Pei Kao1, Chia‐Cheng Chang2, Jau-Nan Lee3, Ming‐Feng Hou1, Cheng‐Yu Long4, Hung-Sheng Chen5, Eing‐Mei Tsai5
1Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA.
3Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
5Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

Tóm tắt

AbstractBackgroundCancer cells are believed to arise primarily from stem cells. CD44+/CD24-have been identified as markers for human breast cancer stem cells. Although, HER2 is a well known breast cancer oncogene, the mechanisms of action of this gene are not completely understood. Previously, we have derived immortal (M13SV1), weakly tumorigenic (M13SV1R2) and highly tumorigenic (M13SV1R2N1) cell lines from a breast epithelial cell type with stem cell phenotypes after successive SV40 large T-antigen transfection, X-ray irradiation and ectopic expression of HER2/C-erbB2/neu. Recently, we found that M13SV1R2 cells became non-tumorigenic after growing in a growth factor/hormone-deprived medium (R2d cells).ResultsIn this study, we developed M13SV1R2N1 under the same growth factor/hormone-deprived condition (R2N1d cells). This provides an opportunity to analyze HER2 effect on gene expression associated with tumorigenesis by comparative study of R2d and R2N1d cells with homogeneous genetic background except HER2 expression. The results reveal distinct characters of R2N1d cells that can be ascribed to HER2: 1) development of fast-growing tumors; 2) high frequency of CD44+/CD24-cells (~50% for R2N1d vs. ~10% for R2d); 3) enhanced expression of COX-2, HDAC6 mediated, respectively, by MAPK and PI3K/Akt pathways, and many genes associated with inflammation, metastasis, and angiogenesis. Furthermore, HER2 expression can be down regulated in non-adhering R2N1d cells. These cells showed longer latent period and lower rate of tumor development compared with adhering cells.ConclusionsHER2 may induce breast cancer by increasing the frequency of tumor stem cells and upregulating the expression of COX-2 and HDAC6 that play pivotal roles in tumor progression.

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Tài liệu tham khảo

Chang CC: Recent translational research: stem cells as the roots of breast cancer. Breast Cancer Res. 2006, 8: 103- 10.1186/bcr1385

Kabil A, Silva E, Kortenkamp A: Estrogens and genomic instability in human breast cancer cells--involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals. Carcinogenesis. 2008, 29: 1862-1868. 10.1093/carcin/bgn138

Bargmann CI, Hung MC, Weinberg RA: The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986, 319: 226-230. 10.1038/319226a0

Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, Saito T, Toyoshima K: Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986, 319: 230-234. 10.1038/319230a0

Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T: The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986, 232: 1644-1646. 10.1126/science.3012781

Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985, 230: 1132-1139. 10.1126/science.2999974

Stern DF, Heffernan PA, Weinberg RA: p185, a product of the neu proto-oncogene, is a receptorlike protein associated with tyrosine kinase activity. Mol Cell Biol. 1986, 6: 1729-1740.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235: 177-182. 10.1126/science.3798106

Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152

Yu D, Hung MC: Role of erbB2 in breast cancer chemosensitivity. Bioessays. 2000, 22: 673-680. 10.1002/1521-1878(200007)22:7<673::AID-BIES10>3.0.CO;2-A

Tan M, Yao J, Yu D: Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res. 1997, 57: 1199-1205.

Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J, Kumar R: Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene. 1999, 18: 305-314. 10.1038/sj.onc.1202307

Dohadwala M, Batra RK, Luo J, Lin Y, Krysan K, Pold M, Sharma S, Dubinett SM: Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion. J Biol Chem. 2002, 277: 50828-50833. 10.1074/jbc.M210707200

Dohadwala M, Luo J, Zhu L, Lin Y, Dougherty GJ, Sharma S, Huang M, Pold M, Batra RK, Dubinett SM: Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem. 2001, 276: 20809-20812. 10.1074/jbc.C100140200

Tsujii M, DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995, 83: 493-501. 10.1016/0092-8674(95)90127-2

Wang KH, Kao AP, Chang CC, Lee JN, Chai CY, Hou MF, Liu CM, Tsai EM: Modulation of tumorigenesis and oestrogen receptor-alpha expression by cell culture conditions in a stem cell-derived breast epithelial cell line. Biol Cell. 2010, 102: 159-172. 10.1042/BC20090132

Hynes NE, Lane HA: ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005, 5: 341-354. 10.1038/nrc1609

Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001, 2: 127-137. 10.1038/35052073

Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL: Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 2002, 62: 4132-4141.

Korkaya H, Paulson A, Iovino F, Wicha MS: HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008, 27: 6120-6130. 10.1038/onc.2008.207

Kao CY, Nomata K, Oakley CS, Welsch CW, Chang CC: Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection. Carcinogenesis. 1995, 16: 531-538. 10.1093/carcin/16.3.531

Chang CC, Sun W, Cruz A, Saitoh M, Tai MH, Trosko JE: A human breast epithelial cell type with stem cell characteristics as target cells for carcinogenesis. Radiat Res. 2001, 155: 201-207. 10.1667/0033-7587(2001)155[0201:AHBECT]2.0.CO;2

Kang KS, Morita I, Cruz A, Jeon YJ, Trosko JE, Chang CC: Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines. Carcinogenesis. 1997, 18: 251-257. 10.1093/carcin/18.2.251

Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE: Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis. 2005, 26: 495-502. 10.1093/carcin/bgh321

Sun W, Kang KS, Morita I, Trosko JE, Chang CC: High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. Cancer Res. 1999, 59: 6118-6123.

Chen H, Campisi J, Padmanabhan R: SV40 large T antigen transactivates the human cdc2 promoter by inducing a CCAAT box binding factor. J Biol Chem. 1996, 271: 13959-13967. 10.1074/jbc.271.24.13959

Tanimoto A, Kao CY, Chang CC, Sasaguri Y, Padmanabhan R: Deregulation of cdc2 gene expression correlates with overexpression of a 110 kDa CCAAT box binding factor in transformed cells. Carcinogenesis. 1998, 19: 1735-1741. 10.1093/carcin/19.10.1735

Kang KS, Sun W, Nomata K, Morita I, Cruz A, Liu CJ, Trosko JE, Chang CC: Involvement of tyrosine phosphorylation of p185(c-erbB2/neu) in tumorigenicity induced by X-rays and the neu oncogene in human breast epithelial cells. Mol Carcinog. 1998, 21: 225-233. 10.1002/(SICI)1098-2744(199804)21:4<225::AID-MC1>3.0.CO;2-J

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003, 100: 3983-3988. 10.1073/pnas.0530291100

Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004, 6: R605-615. 10.1186/bcr920

Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS: A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol. 2005, 277: 443-456. 10.1016/j.ydbio.2004.07.044

Liu S, Dontu G, Wicha MS: Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 2005, 7: 86-95. 10.1186/bcr1021

Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J: Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002, 62: 632-635.

Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ: HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res. 2006, 66: 5504-5511. 10.1158/0008-5472.CAN-05-4076

Minucci S, Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006, 6: 38-51. 10.1038/nrc1779

Lee YS, Lim KH, Guo X, Kawaguchi Y, Gao Y, Barrientos T, Ordentlich P, Wang XF, Counter CM, Yao TP: The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res. 2008, 68: 7561-7569. 10.1158/0008-5472.CAN-08-0188

Valenzuela-Fernandez A, Cabrero JR, Serrador JM, Sanchez-Madrid F: HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol. 2008, 18: 291-297. 10.1016/j.tcb.2008.04.003

Tran AD, Marmo TP, Salam AA, Che S, Finkelstein E, Kabarriti R, Xenias HS, Mazitschek R, Hubbert C, Kawaguchi Y: HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J Cell Sci. 2007, 120: 1469-1479. 10.1242/jcs.03431

Zhang X, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, Olashaw N, Parsons JT, Yang XJ, Dent SR: HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell. 2007, 27: 197-213. 10.1016/j.molcel.2007.05.033

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007, 1: 555-567. 10.1016/j.stem.2007.08.014

Beuzeboc P, Scholl S, Garau XS, Vincent-Salomon A, Cremoux PD, Couturier J, Palangie T, Pouillart P: Herceptin, a monoclonal humanized antibody anti-HER2: a major therapeutic progress in breast cancers overexpressing this oncogene?. Bull Cancer. 1999, 86: 544-549.

Howe LR: Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res. 2007, 9: 210- 10.1186/bcr1678

Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H: Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res. 2005, 11: 1154-1159.

Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG: Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2-cancer cells are similarly tumorigenic. Cancer Res. 2005, 65: 6207-6219. 10.1158/0008-5472.CAN-05-0592

Nakanishi T, Chumsri S, Khakpour N, Brodie AH, Leyland-Jones B, Hamburger AW, Ross DD, Burger AM: Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling. Br J Cancer. 2010, 102: 815-826. 10.1038/sj.bjc.6605553

Saji S, Kawakami M, Hayashi S, Yoshida N, Hirose M, Horiguchi S, Itoh A, Funata N, Schreiber SL, Yoshida M, Toi M: Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene. 2005, 24: 4531-4539. 10.1038/sj.onc.1208646

Collins NL, Reginato MJ, Paulus JK, Sgroi DC, Labaer J, Brugge JS: G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. Mol Cell Biol. 2005, 25: 5282-5291. 10.1128/MCB.25.12.5282-5291.2005

Allan AL, Vantyghem SA, Tuck AB, Chambers AF: Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis. 2006, 26: 87-98.

Chong CR, Chabner BA: Mysterious metformin. Oncologist. 2009, 14: 1178-1181. 10.1634/theoncologist.2009-0286

Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K: Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009, 69: 7507-7511. 10.1158/0008-5472.CAN-09-2994

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009, 138: 645-659. 10.1016/j.cell.2009.06.034

Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D: CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest. 2010, 120: 485-497. 10.1172/JCI39397

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