Prevention of Breast Cancer Cell Transformation by Blockade of the AP-1 Transcription Factor.

摘要

We are investigating the role of AP-1 in controlling breast cell growth and transformation. We propose 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 AP-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 AP-1 protein 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 AP-1 for growth in serum. We also present results showing that inhibition of AP-i completely blocked MCF7 proliferation induced by IGF-1 and EGF, yet only partially inhibited growth induced by estrogen. These results demonstrated that the nitrogenic pathways in MCF7 cells activated by serum, estrogen, IGF-1, and EGF depend on AP-1 to transduce a proliferative signal, and that estrogen partially overcomes the growth suppressive effect of AP-1 blockade. These results suggest that AP-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.