Effects of female hormone withdrawal and ulipristal acetate on MED12 mutation-positive and  -negative uterine leiomyomas using a xenograft model
The effects of therapeutic drugs that inhibit female hormone functions on uterine leiomyomas (ULMs) vary among individuals. ULMs are classified into two subtypes with different histological compositions: MED12 mutation-positive and -negative ULMs. The present study was undertaken to investigate the tumor regression effects of female hormone withdrawal and a selective progesterone (P) receptor modulator (ulipristal acetate, UPA) in the ULM subtypes using a xenograft mouse model. Smooth muscle cells (SMCs) isolated from each ULM subtype were transplanted and treated with estrogen (E) and P for 4 weeks to form the xenograft tumor. They were then divided into four groups: continued EP treatment (E(+)P(+)), EP withdrawal (E(-)P(-)), only P withdrawal (E(+)P(-)), and EP+UPA. Tumors were harvested 8 weeks after transplantation. In both subtypes, they were reduced in size in the E(-)P(-) compared with the E(+)P(+) and further reduced in the EP+UPA. Histological analysis showed that SMCs shrank in the E(-)P(-) and disappeared in the EP+UP. Since there were no histological differences between the subtypes, comprehensive gene expression and pathway analyses were performed. Gene ontology and pathway analyses of the differentially expressed genes of the xenograft tumors suggested that regression occurred by different mechanisms in the two subtypes. Our results also suggested, for the first time, that UPA caused SMC death by a mechanism other than progesterone receptor inhibition.