Abstract
The progesterone receptor (PR) expression is associated with disease-free survival in breast cancer. Yet, PR is known to elicit the activation of pro-tumor or anti-tumor signalling pathways. To gain a comprehensive understanding of intrinsic activities of PR, we conducted a global profiling of PR-regulated proteins using Tandem Mass Tag (TMT) proteomics in MCF-7 cells with elevated PR levels. The analysis identified reliably and reproducibly 4,915 PR-regulated proteins and 678 phosphorylated peptides in response to progestin R5020. Consistent with its growth inhibitory activity, PR broadly reduced levels of proteins for cell division, including CDKs, cyclins, DNA replication factors, and proteins involved in chromatin condensation, spindle assembly and chromosome segregation. PR also induced previously reported upregulation of pro-growth proteins such as EGFR, IRS2, and CCND1, but the upregulations are functionally futile due partly to inhibitory phosphorylation. Importantly, PR regulated 200 mitochondrial proteins including proapoptotic factors BNIP3, NIX, AIF/AIFM1, AIFM2, ENDOG, HtrA2/Omi, and Smac/DIABLO, culminating in mitochondria-mediated apoptosis independent of caspases. In conclusion, this proteomics study achieved to date the most comprehensive understanding of PR-regulated molecular networks that are strongly anti-proliferative and proapoptotic with pivotal involvement of mitochondria. PR agonists warrant evaluation for the treatment of breast cancer with high PR expression.