Abstract
The activating protein-1 (AP-1) transcription factor is a converging point of multiple signal transduction pathways in many cells. We have previously demonstrated that overexpressing Tam67, a dominant-negative (DN) form of cJun, blocks AP-1 activity and inhibits breast cancer cell growth. We hypothesized that Tam67 forms dimers with other AP-1 proteins to suppress the growth of breast cancer cells. In the present study, we used immunoprecipitation-Western blotting to demonstrate that Tam67 binds all Jun and Fos proteins in breast cancer cells. In addition, we used two variants of the Tam67 mutant to investigate whether Jun or Fos protein was required for breast cancer cell growth. We created a Tam/Fos mutant in which the cJun dimerization domain was replaced by the cFos dimerization domain, and a Tam/Squelcher mutant in which the cJun dimerization domain was deleted. We then isolated MCF-7 cell lines that stably expressed these cJun-DN mutants under the control of an inducible promoter. Using AP-1-dependent reporter assays, we observed that Tam67 and Tam/Fos mutants inhibited AP-1 transcriptional activity, while the Tam/Squelcher mutant did not. We then determined whether Tam/Fos or Tam/Squelcher inhibited breast cell growth as well as Tam67. We found that while Tam67 repressed cell growth, neither Tam/Fos nor Tam/Squelcher mutant affected cell growth. These results indicate that Tam67 likely inactivates Fos family member proteins to suppress breast cancer cell growth. Finally, we performed antisense experiments to knock down the expression of individual family members (cJun or cFos). Our results demonstrated that antisense cFos inhibited breast cancer cell proliferation and colony formation, while antisense cJun did not. These results suggest that Tam67 suppresses breast cancer cell growth by interacting with Fos family members, specifically with cFos, to produce an inactive AP-1 complex.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- ATF:
-
activating transcription factor
- AP-1:
-
activating protein-1
- Tam67:
-
cJun dominant-negative mutant
- DOX:
-
doxycycline
- HRG-β:
-
heregulin-beta
- TPA:
-
phorbol 12-O-tetradecanoate-13-acetate
References
Alani R, Brown P, Binetruy B, Dosaka H, Rosenberg RK, Angel P, Karin M and Birrer MJ . (1991). Mol. Cell. Biol., 11, 6286–6295.
Angel P, Baumann I, Stein B, Delius H, Rahmsdorf HJ and Herrlich P . (1987). Mol. Cell. Biol., 7, 2256–2266.
Angel P and Karin M . (1991). Biochim. Biophys. Acta, 1072, 129–157.
Aronheim A, Zandi E, Hennemann H, Elledge SJ and Karin M . (1997). Mol. Cell. Biol., 17, 3094–3102.
Arteaga CL and Holt JT . (1996). Cancer Res., 56, 1098–1103.
Bamberger AM, Methner C, Lisboa BW, Stadtler C, Schulte HM, Loning T and Milde-Langosch K . (1999). Int. J. Cancer, 84, 533–538.
Barber JR and Verma IM . (1987). Mol. Cell. Biol., 7, 2201–2211.
Bland KI, Konstadoulakis MM, Vezeridis MP and Wanebo HJ . (1995). Ann. Surg., 221, 706–718; discussion 718–720.
Brown PH, Alani R, Preis LH, Szabo E and Birrer MJ . (1993). Oncogene, 8, 877–886.
Brown PH, Chen TK and Birrer MJ . (1994). Oncogene, 9, 791–799.
Brown PH, Kim SH, Wise SC, Sabichi AL and Birrer MJ . (1996). Cell Growth Differ., 7, 1013–1021.
Chen TK, Smith LM, Gebhardt DK, Birrer MJ and Brown PH . (1996). Mol. Carcinogen., 15, 215–226.
Chiu R, Angel P and Karin M . (1989). Cell, 59, 979–986.
Daschner PJ, Ciolino HP, Plouzek CA and Yeh GC . (1999). Breast Cancer Res. Treat., 53, 229–240.
DeNardo DG, Kim HT, Hilsenbeck S, Cuba V, Tsimelzon A and Brown PH . (2005). Mol. Endocrinol., 19, 362–378.
Gajate C, Alonso MT, Schimmang T and Mollinedo F . (1996). Biochem. Biophys. Res. Commun., 218, 267–272.
Gee JM, Barroso AF, Ellis IO, Robertson JF and Nicholson RI . (2000). Int. J. Cancer, 89, 177–186.
Gee JM, Ellis IO, Robertson JF, Willsher P, McClelland RA, Hewitt KN, Blamey RW and Nicholson RI . (1995). Int. J. Cancer, 64, 269–273.
Ham J, Babij C, Whitfield J, Pfarr CM, Lallemand D, Yaniv M and Rubin LL . (1995). Neuron, 14, 927–939.
Hennigan RF and Stambrook PJ . (2001). Mol. Biol. Cell, 12, 2352–2363.
Holt JT, Gopal TV, Moulton AD and Nienhuis AW . (1986). Proc. Natl. Acad. Sci. USA, 83, 4794–4798.
Johnston SR, Lu B, Scott GK, Kushner PJ, Smith IE, Dowsett M and Benz CC . (1999). Clin. Cancer Res., 5, 251–256.
Karin M, Liu Z and Zandi E . (1997). Curr. Opin. Cell Biol., 9, 240–246.
Lin F, Xiao D, Kolluri SK and Zhang X . (2000). Cancer Res., 60, 3271–3280.
Liu Y, Lu C, Shen Q, Munoz-Medellin D, Kim H and Brown PH . (2004). Oncogene, 23, 8238–8246.
Liu Y, Ludes-Meyers J, Zhang Y, Munoz-Medellin D, Kim HT, Lu C, Ge G, Schiff R, Hilsenbeck SG, Osborne CK and Brown PH . (2002). Oncogene, 21, 7680–7689.
Ludes-Meyers JH, Liu Y, Munoz-Medellin D, Hilsenbeck SG and Brown PH . (2001). Oncogene, 20, 2771–2780.
Mackay AR, Ballin M, Pelina MD, Farina AR, Nason AM, Hartzler JL and Thorgeirsson UP . (1992). Invasion Metast., 12, 168–184.
Matrisian LM . (1994). Ann. NY Acad. Sci., 732, 42–50.
McDonnell SE, Kerr LD and Matrisian LM . (1990). Mol. Cell. Biol., 10, 4284–4293.
Nishikura K and Murray JM . (1987). Mol. Cell. Biol., 7, 639–649.
Piechaczyk M and Blanchard JM . (1994). Crit. Rev. Oncol. Hematol., 17, 93–131.
Piu F, Aronheim A, Katz S and Karin M . (2001). Mol. Cell. Biol., 21, 3012–3024.
Preston GA, Lyon TT, Yin Y, Lang JE, Solomon G, Annab L, Srinivasan DG, Alcorta DA and Barrett JC . (1996). Mol. Cell. Biol., 16, 211–218.
Riabowol KT, Vosatka RJ, Ziff EB, Lamb NJ and Feramisco JR . (1988). Mol. Cell. Biol., 8, 1670–1676.
Robinson-Benion C, Li YX and Holt JT . (1994). Leukemia, 8 (Suppl 1), S152–S155.
Rodgers WH, Matrisian LM, Giudice LC, Dsupin B, Cannon P, Svitek C, Gorstein F and Osteen KG . (1994). J. Clin. Invest., 94, 946–953.
Roffler-Tarlov S, Brown JJ, Tarlov E, Stolarov J, Chapman DL, Alexiou M and Papaioannou VE . (1996). Development, 122, 1–9.
Schiff R, Reddy P, Ahotupa M, Coronado-Heinsohn E, Grim M, Hilsenbeck SG, Lawrence R, Deneke S, Herrera R, Chamness GC, Fuqua SA, Brown PH and Osborne CK . (2000). J. Natl. Cancer Inst., 92, 1926–1934.
Schule R, Rangarajan P, Yang N, Kliewer S, Ransone LJ, Bolado J, Verma IM and Evans RM . (1991). Proc. Natl. Acad. Sci. USA, 88, 6092–6096.
Schutte J, Viallet J, Nau M, Segal S, Fedorko J and Minna J . (1989). Cell, 59, 987–997.
Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, Brown PH and Birrer MJ . (1999). Oncogene, 18, 6063–6070.
Szabo E, Preis LH, Brown PH and Birrer MJ . (1991). Cell Growth Differ., 2, 475–482.
Tang Z, Treilleux I and Brown M . (1997). Mol. Cell. Biol., 17, 1274–1280.
Vogt PK and Bos TJ . (1990). Adv. Cancer Res., 55, 1–35.
Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E, Katzenellenbogen BS, Enmark E, Gustafsson JA, Nilsson S and Kushner PJ . (1999). Mol. Endocrinol., 13, 1672–1685.
Yoshioka K, Deng T, Cavigelli M and Karin M . (1995). Proc. Natl. Acad. Sci. USA, 92, 4972–4976.
Acknowledgements
We thank Tibor Krisko, Tracy Strecker, and David DeNardo for their helpful discussions and critical review of this manuscript. We would also like to thank Shirley Pennington for her assistance in preparing this manuscript. This work was supported by the Department of Defense grant (DAMD-17-96-1-6225 to PHB) and the Department of Defense Postdoctoral Fellowship Award (DAMD17-01-1-0701 to CL).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lu, C., Shen, Q., DuPré, E. et al. cFos is critical for MCF-7 breast cancer cell growth. Oncogene 24, 6516–6524 (2005). https://doi.org/10.1038/sj.onc.1208905
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208905
Keywords
This article is cited by
-
Selective antagonism of cJun for cancer therapy
Journal of Experimental & Clinical Cancer Research (2020)
-
Signal-induced PARP1-Erk synergism mediates IEG expression
Signal Transduction and Targeted Therapy (2019)
-
γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells
Tumor Biology (2016)
-
Free Energy of Binding of Coiled-Coil Complexes with Different Electrostatic Environments: The Influence of Force Field Polarisation and Capping
Natural Products and Bioprospecting (2014)
-
RETRACTED ARTICLE: Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy
Breast Cancer Research (2013)