Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

AP-1 blockade inhibits the growth of normal and malignant breast cells

Abstract

We have previously demonstrated that basal AP-1 transcriptional activity is high in normal human mammary epithelial cells, intermediate in immortal breast cells, and relatively low in breast cancer cells. In this study we investigated whether differences in AP-1 transcriptional activity reflect differences in breast cells' dependence on AP-1 for proliferation. The cJun dominant negative, TAM-67, was used to determine the effect of AP-1 blockade on the growth of normal, immortal and malignant breast cells. We first showed that TAM-67 inhibits AP-1 activity in normal and malignant breast cells. We then determined whether this AP-1 inhibitor affected colony forming efficiency of the immortalized and malignant breast cells. The AP-1 inhibitor reduced colony formation of immortal breast cells by over 50% (by 58% in 184B5 cells and 62% in MCF10A cells), and reduced colony formation in the breast cancer cell line MCF7 by 43%, but did not reduce colony formation in the other breast cancer cell lines (T47D, MDA MB231 and MDA MB 435). We also determined the effect of AP-1 blockade on the growth of normal breast cells using a single cell proliferation assay. Using this assay, the growth of normal breast cells was extremely sensitive to AP-1 blockade, while immortal breast cells were moderately sensitive. We next directly tested the effect of TAM-67 expression on the growth of MCF7 breast cancer cells, using cells stably transfected with TAM-67 under the control of a doxycycline-inducible promoter. Upon induction, TAM-67 was expressed and AP-1 activity was inhibited in these cells. We then measured the growth of these cells in the presence or absence of TAM-67. The results of these studies show that the growth of MCF7 cells was suppressed by the AP-1 inhibitor, TAM-67. These results demonstrate that normal and immortalized breast cells, and some breast cancer cells (such as MCF7), require AP-1 to transduce proliferative signals, while other breast cancer cells (such as T47D, MDA MB 231 and MDA MB 435) do not. These studies suggest that the AP-1 transcription factor is a potential target for future agents for the prevention or treatment of breast cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Nadia Harbeck, Frédérique Penault-Llorca, … Fatima Cardoso

Abbreviations

AP-1:

Activating Protein-1

ER:

Estrogen receptor

HMECs:

Human mammary epithelial cells

IGF:

insulin-like growth factor

SCPA:

Single cell proliferation assay

SEM:

standard error of the mean

TGFα:

transforming growth factor alpha

TPA:

12-O-tetradecanoylphorbol-13-acetate

X-Gal:

5-Bromo-4-Chloro-3-Indoyl-ß-galactopyranoside.

References

  • Bamberger A, Methner C, Lisboa B, Stadler C, Schulte H, Loning T, Milde-Langosch K . 1999 Int. J. Cancer 84: 533–538

  • Baselga J, Mendelsohn J . 1994 Breast Cancer Res. Treat. 29: 127–138

  • Berenblum I, Shubik P . 1947 Br. J. Cancer 1: 379–383

  • Bishop J . 1987 Science 235: 305–311

  • Bonsing BA, Corver WE, Gorsira MC, Vliet MV, Oud PS, Cornelisse CJ, Fleuren GJ . 1997 Cytometry 28: 11–24

  • Box GEP, Cox DR . 1962 J. R. Statist. Soc. 26: 211–256

  • Brown PH, Alani R, Preis LH, Szabo E, Birrer MJ . 1993 Oncogene 8: 877–886

  • Chen TK, Smith LM, Gebhardt DK, Birrer MJ, Brown PH . 1996 Mol. Carcinog. 15: 215–226

  • Ciardiello F, McGeady ML, Kim N, Basolo F, Hynes N, Langton B, Yokozaki H, Saiki T, Elliott J, Hasui H, Mendelsohn J, Soule H, Russo J, Salomon DS . 1990 Cell Growth Diff. 1: 407–420

  • Domann FE, Levy JP, Birrer MJ, Bowden GT . 1994 Cell Growth Diff. 5: 9–16

  • Dong Z, Birrer MJ, Watts RG, Matrisian LM, Colburn NH . 1994 Proc. Natl. Acad. Sci. USA 91: 609–613

  • Gee J, Barroso A, Ellis I, Robertson J, Nicholson R . 2000 Int. J. Cancer 89: 177–186

  • Ham J, Babij C, Whitfield J, Pfarr CM, Lallemand D, Yaniv M, Rubin LL . 1995 Neuron 14: 927–939

  • Harris J, Morrow M, Bodadonna G . 1993 Cancer of the Breast. Devita J (ed) Lippincott Co.: Philadelphia pp. 1264–1332

  • Karin M, Liu Z, Zandi E . 1997 Curr. Opin. Cell Biol. 9: 240–246

  • Katayose D, Gudas J, Nguyen H, Srivastava S, Cowan KH, Seth P . 1995 Clin. Cancer Res. 8: 889–897

  • Kovary K, Bravo R . 1991 Mol. Cell. Biol. 11: 4466–4472

  • Landis S, Murray T, Bolden S, Wingo P . 1999 CA Cancer J. Clin. 49: 8–31

  • Lehman TA, Modali R, Boukamp P, Stanek J, Bennett WP, Welsh JA, Metcalf RA, Stampfer MR, Fusenig N, Rogan EM, Harris CC . 1993 Carcinogenesis 14: 833–839

  • Lesoon-Wood LA, Kim WH, Kleinman HK, Weintraub BD, Mixson AJ . 1995 Hum. Gene Ther. 4: 395–405

  • Malkin D, Lee FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Freind SH . 1990 Science 250: 1233–1238

  • Petrak D, Memon SA, Birrer MJ, Ashwell JD, Zacharchuk CM . 1994 J. Immunol. 152: 2046–2051

  • Smith LM, Birrer MJ, Stampfer MR, Brown PH . 1997 Cancer Res. 57: 3046–3054

  • Soule HD, Maloney TM, Wolman SR, Peterson WD, Brenz R, McGrath CM, Russo J, Pauley RJ, Jones RF, Brooks SC . 1990 Cancer Res. 50: 6075–6086

  • Stampfer M, Hallowes RC, Hackett AJ . 1980 In Vitro 16: 415–425

  • Stampfer M, Yaswen P . 1992 Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms. Milo G, Casto B and Shuler C. (eds). CRC Press: Boca Raton pp. 117–139

  • Stampfer MR, Bartley JC . 1985 Proc. Natl. Acad. Sci. USA 82: 2394–2398

  • Stampfer MR, Pan CH, Hosoda J, Bartolomew J, Mendelsohn J, Yaswen P . 1993 Exp. Cell Res. 209: 175–188

  • Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ . 1996 Genes Dev. 10: 804–815

  • Tripathy D, Benz CC . 1993 Activated Oncogenes and Putative Tumor Suppressor Genes Involved in Human Breast Cancer. Benz L. (ed.) Kluwer Academic Publishers: Boston MA pp. 15–60

  • Yoshioka K, Deng T, Cavigelli M, Karin M . 1995 Proc. Natl. Acad. Sci. USA 92: 4972–4976

  • Zajchowski D, Band V, Pauzie N, Tager A, Stampfer M, Saager R . 1988 Cancer Res. 48: 7041–7047

Download references

Acknowledgements

The authors would like to acknowledge Dr Martha Stampfer for providing normal and immortal human mammary epithelial cells. In addition, we would like to thank Paula Sauceda, Dr Chunhua Lu and Kendall Wu for their assistance in preparing this manuscript. This work was supported by Department of Defense grant DAMD-17-96-1-6225 (PH Brown, YM Liu, D Muñoz-Medellin). JH Ludes-Meyers was supported by National Institutes for Health training program for translational breast cancer grant #CA70091.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Powel H Brown.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ludes-Meyers, J., Liu, Y., Muñoz-Medellin, D. et al. AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene 20, 2771–2780 (2001). https://doi.org/10.1038/sj.onc.1204377

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204377

Keywords

This article is cited by

Search

Quick links