Abstract
Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3–Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.
Similar content being viewed by others
References
Alas S, Bonavida B . 2001 Cancer Res. 61: 5137–5144
Bargou RC, Daniel PT, Mapara MY, Bommert K, Wagener C, Kallinich B, Royer HD, Dorken B . 1995 Int. J. Cancer 60: 854–859
Bartucci M, Morelli C, Mauro L, Ando S, Surmacz E . 2001 Cancer Res. 61: 6747–6754
Benito A, Grillot D, Nunez G, Fernandez-Luna JL . 1995 Am. J. Pathol. 146: 481–490
Benito A, Silva M, Grillot D, Núñez G, Fernandez-Luna JL . 1996 Blood 87: 3837–3843
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE . 1999 Cell 98: 295–303
Bruns CJ, Solorzano CC, Harbison MT, Ozawa S, Tsan R, Fan D, Abbruzzese J, Traxler P, Buchdunger E, Radinsky R, Fidler IJ . 2000 Cancer Res. 60: 2926–2935
Bundred N, Chan K, Anderson N . 2001 Endocr.-Relat. Cancer 8: 183–189
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . 1999 Immunity 10: 105–115
Del Bufalo D, Biroccio A, Leonetti C, Zupi G . 1997 FASEB J. 11: 947–953
Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M, Samudio I, Kladde MP, Vyhlidal C, Safe S . 1999 J. Biol. Chem. 274: 32099–32107
Ellis PA, Smith I, Detre S, Burton S, Salter J, A'Hern R, Walsh G, Johnston SR, Dowsett M . 1998 Breast Cancer Res. Treat. 48: 107–116
Fernandes A, Hamburger AW, Gerwin BI . 1999 Int. J. Cancer 83: 564–570
Fernandez Y, Espana L, Manas S, Fabra A, Sierra A . 2000 Cell Death Differ. 7: 350–359
Fry D, Bridges A, Denny W, Doherty A, Greis K, Hicks J, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM . 1998 Proc. Natl. Acad. Sci. USA 95: 12022–12027
Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R . 2001 Oncogene 20: 2499–2513
Garcia R, Yu C-L, Hudnall A, Catlett R, Nelson K, Smithgall T, Fujita DJ, Ethier SP, Jove R . 1997 Cell Growth Differ. 8: 1267–1276
Glinsky GV, Glinsky VV, Ivanova A, Hueser CJ . 1997 Cancer Lett. 1115: 185–193
Harris AL, Nicholson S, Sainsbury R, Wright C, Farndon J . 1992 J. Natl. Cancer Inst. Monogr. 11: 181–187
Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL . 2000 J. Exp. Med. 191: 977–984
Jaattela M . 1999 Exp. Cell Res. 248: 30–43
Krajewski S, Krajewska M, Turner BC, Pratt C, Howard B, Zapata JM, Frenkel V, Robertson S, Ionov Y, Yamamoto H, Perucho M, Takayama S, Reed JC . 1999 Endocr.-Relat. Cancer 6: 29–40
Kumar R, Mandal M, Lipton A, Harvey H, Thompson CB . 1996 Clin. Cancer Res. 2: 1215–1219
Ma L, Gauville C, Berthois Y, Degeorges A, Millot G, Martin PM, Calvo F . 1998 Int. J. Cancer 78: 112–119
Mayo MW, Wang CY, Drouin S, Madrid L, Marshall A, Reed JC, Weissman BE, Baldwin AS . 1999 EMBO J. 18: 3990–4003
Nakamura N, Chin H, Miyasaka N, Miura O . 1996 J. Biol. Chem. 271: 19483–19488
Nicolson GL . 1993 Cancer Metastasis Rev. 12: 325–343
Perillo B, Sasso A, Abbodanza C, Palumbo G . 2000 Mol. Cell. Biol. 20: 2890–2901
Price JE, Polyzos A, Zhang RD, Daniels L . 1990 Cancer Res. 50: 717–721
Sanz C, Benet I, Richard C, Badia B, Andreu EJ, Prosper F, Fernandez-Luna JL . 2001 Exp. Hematol. 29: 728–735
Schorr K, Li M, Bar-Peled U, Lewis A, Heredia A, Lewis B, Knudson CM, Korsmeyer SJ, Jager R, Weiher H, Furth PA . 1999 Cancer Res. 59: 2541–2545
Sierra A, Castellsague X, Escobedo A, Lloveras B, Garcia-Ramirez M, Moreno A, Fabra A . 2000 Int. J. Cancer 89: 142–147
Sierra A, Castellsague X, Tortola S, Escobedo A, Lloveras B, Peinado MA, Moreno A, Fabra A . 1996 Clin. Cancer Res. 2: 1887–1894
Sierra A, Price JE, Garcia-Ramirez M, Mendez O, Lopez L, Fabra A . 1997 Lab. Invest. 77: 357–368
Silberstein G, Van Horn K, Strickland P, Roberts R, Daniel C . 1997 Proc. Natl. Acad. Sci. USA 94: 8132–8137
Silva M, Benito A, Sanz C, Prosper F, Ekhterae D, Nuñez G, Fernandez-Luna JL . 1999 J. Biol. Chem. 274: 22165–22169
Stephanou A, Brar B, Knight R, Latchman D . 2000 Cell Death Differ. 7: 329–330
Wells A . 1999 Int. J. Biochem. Cell. Biol. 31: 637–643
Wilson BE, Mochon E, Boxer LM . 1996 Mol. Cell. Biol. 16: 5546–5556
Wu J . 1996 Anticancer Res. 16: 2233–2239
Yarden RI, Wilson MA, Chrysogelos SA . 2001 J. Cell. Biochem. 36: 232–246
Yu D, Liu B, Tan M, Li J, Wang SS, Hung MC . 1996 Oncogene 13: 1359–1365
Zhong H, Minneman KP . 1999 Biochem. J. 344: 889–894
Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH . 2000 J. Biol. Chem. 275: 15099–15105
Acknowledgements
We thank Richard Jove and James Darnell for providing Stat3 expression vectors, and I Orman for excellent technical assistance. This work was supported by Comision Interministerial de Ciencia y Tecnologia Grant No. SAF99-0139 and by a grant from the ‘Fundacion Marcelino Botin’ (proyecto Terapia Genica) to JL Fernandez-Luna. PJ Real is a recipient of a predoctoral fellowship from the ‘Fundacion Ramon Areces’.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Real, P., Sierra, A., de Juan, A. et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 21, 7611–7618 (2002). https://doi.org/10.1038/sj.onc.1206004
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206004
- Springer Nature Limited
Keywords
This article is cited by
-
Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression
Cell Communication and Signaling (2021)
-
Glioblastoma invasion factor ODZ1 is induced by microenvironmental signals through activation of a Stat3-dependent transcriptional pathway
Scientific Reports (2021)
-
10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation
Acta Pharmacologica Sinica (2021)
-
Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells
Oncogenesis (2021)
-
Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells
BMC Cancer (2020)