Prevention of Breast Cell Transformation by Blockade of the AP-l Transcription Factor (95 Breast)

摘要

We are investigating the role of AP- 1 in controlling breast cell growth and transformation. We proposed to determine the role of the AP- 1 family of transcription factors in mediating peptide growth factor-induced proliferation and oncogene-induced transformation of breast cells. Previous results demonstrated that Al)- 1 complexes are activated by peptide and steroid growth factors in normal and malignant breast cells, and that normal breast cells express higher levels of Al)- I proteins and activity than do breast cancer cells. We also previously showed that normal and immortal cells are more dependent on AP-1 for their growth than are most breast cancer cells. Over the last year, we determined whether AP-1 activation is required to transduce growth factor-induced signals in breast cancer cells. To perform these studies, we isolated MCF7 and MDA MB 435 clones that express a dominant-negative cJun mutant (TAM-67) under the control of an inducible promoter. These studies demonstrated that MCF7 cells, but not MDA MB 435 cells, depend on Al)- 1 for growth in serum. We also present results showing that inhibition of Al>- 1 completely blocked MCF7 proliferation induced by lGF- 1 and EGF, yet only partially inhibited growth induced by estrogen. These results demonstrate that the mitogenic pathways in MCF7 cells activated by serum, estrogen, IGF- 1, and EGF depend on Al)- 1 to transduce a proliferative signal, and that estrogen partially overcomes the growth suppressive effect of Al)- 1 blockade. These results suggest that Al)- 1 is a promising target of future cancer therapeutic and preventive agents since blocking this critical transcription factor suppresses proliferation induced by multiple growth factors.