Differential regulation of AP1 activity by retinoic acid in hormone-dependent and -independent breast cancer cells.
We have studied the role of the AP1 transcription factor in the progression of human breast carcinomas. This progression is characterized by a loss of dependence for proliferation on mitogenic hormones, and is also linked to loss of responsiveness to the growth inhibitor retinoic acid (RA). In the hormone-dependent breast tumor cell line MCF7 mitogenic stimulation was found to be linked to an enhancement of AP1 transcriptional activity, while growth inhibition by RA was parallelled by decreased AP1 activity. AP1 binding activity to its consensus DNA sequence was rapidly reduced in RA treated cells, in the absence of any noticeable change in expression of AP1 constituents. AP1 overexpression abrogated RA repression in MCF7 cells. In hormone-independent cell lines (BT20, Hs578T, MDA-MB231, MDA-MB468) autonomous proliferation was associated with an increased background AP1 activity. Interestingly, these cells are refractory to growth inhibition by RA, which can only be partly explained by underexpression of RA receptors. In these cells RA did not repress AP1 transactivation unless RA receptors were overexpressed by means of cotransfection with an expression vector. This suggests that the high background levels of AP1 activity in the autonomously growing cells are associated with prevention of RA inhibition of AP1 activity to occur. Therefore, increased AP1 activity may not only play a role in progression of breast tumors towards hormone-insensitivity but may also contribute to the RA resistance of such cells.
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D016384:Consensus Sequence; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006728:Hormones; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D014212:Tretinoin