Medroxyprogesterone (MPA) has
therapeutic effect on
endometrial carcinoma (EC), while it could promote the
carcinogenesis of
breast cancer (BC) by activating receptor activator of
NF-kB ligand (RANKL). However, the selective mechanism of MPA in endometrium and breast tissue remains obscure. Multiomics analysis of
chromatin immunoprecipitation sequencing (ChIP-seq) and
RNA sequencing (
RNA-seq) were performed in cell lines derived from
endometrial cancer and mammary
tumor to screen the differential co-regulatory factors of
progesterone receptor (PR). Dual-
luciferase assays and ChIP-PCR assays were used to validate the transcriptional regulation. Co-immunoprecipitation (Co-IP) and immunofluorescence assays were carried out to explore molecular interactions between PR, the cofactor transcriptional repressor GATA binding 1 (TRPS1), and
histone deacetylase 2 (HDAC2). Subsequently, human
endometrial cancer/
breast cancer xenograft models were established to investigate the regulation effect of cofactor TRPS1 in vivo. In the current study, we found that MPA downregulated RANKL expression in a time- and dose-dependent manner in EC, while had the opposite effect on BC. Then PR could recruit cofactor TRPS1 to the promoter of RANKL, leading to
histone deacetylation of RANKL to repress its transcription in EC, whereas MPA disassociated the PR/TRPS1/HDAC2 complex to enhance RANKL
histone acetylation in BC. Therefore, TRPS1, the coregulator recruited by PR played a critical role in the selective mechanism of
progesterone in EC and BC and could become a potential candidate for targeted
therapy to improve the anticancer effect of MPA on EC and avoid its carcinogenic effect on BC.