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