New pathway links from cancer-progression determinants to gene expression of matrix metalloproteinases in breast cancer cells.

AP-2alpha, interleukin-4 (IL-4), E-cadherin, fibulin 1D, p16(INK4alpha), PTEN, RKIP, and S100A4 are determinants (suppressors, except for S100A4) of cancer cell invasiveness and other traits of cancer progression, which are located upstream of matrix metalloproteinases (MMPs) in cell signaling pathways. We will refer to them as upstream cancer-progression determinants (UCPDs, for brevity). MMP-1, MMP-2, MMP-9, MMP-11, MMP-13, MMP-14, MMP-16, and MMP-19 are enhancers of cancer cell invasiveness and other traits of cancer progression, in MDA-MB-231 breast cancer cells. We are interested in pathway links from UCPDs to gene expression of cancer cell MMPs in MDA-MB-231 cells. To test models about these links, wild-type copies of UCPDs were transiently overexpressed and then MMP mRNAs were measured by reverse transcription real-time PCR. The present results show that each of eight UCPDs is linked to the gene expression of a unique set of MMPs. This indicates that the effects are sequence-specific and that each UCPD reaches these MMP expressions through different sets of signaling pathways. We have detected 20 new pathway links, 11 are downregulatory and nine are upregulatory; 15 are new links in any cell, and five are new links in breast cancer. In seven links, three cancer-progression suppressing UCPDs unexpectedly enhance the gene expression of five cancer-progression promoting MMPs.