Progesterone receptor A and B expression and progestagen treatment in growth and spread of endometrial cancer cells in nude mice

Abstract

In endometrial cancer, decreased expression of progesterone receptor (PR) isotypes A and B (PRA and PRB) is a feature of poorly differentiated tumours. In distant metastases, PRB is the predominantly expressed isotype and endometrial cancer cells that express PRB have been observed to be more invasive. Furthermore, PRB-associated in vitro invasion is markedly inhibited by progestagens.In the present study, ovariectomized mice were injected intraperitoneally with Ishikawa endometrial cancer cells that express only PRA, only PRB, both PRA and PRB, or no PR. Half of the mice were substituted with medroxyprogesterone acetate (MPA). After ten weeks, growth and spread of the cancer cells were examined macroscopically, microscopically, and by PCR detection. Without MPA substitution, cells that express only PRB were found to be the most proliferative and migrative, while cells that express only PRA, both receptor isotypes, or no PR, showed minimal growth and spread. MPA appeared to inhibit growth and spread of PR-positive cells. Surprisingly, when mice that were inoculated with PR-negative cells were substituted with MPA, this resulted in massive abdominal tumour growth.These results provide further evidence that over-expression of PRB in endometrial cancer contributes to the development of a more aggressive phenotype. MPA inhibits tumour growth and spread of PR-positive cells, but can also have an indirectly stimulating effect on PR-negative tumour cells, probably through a host-mediated response.

Endometrial miR-181a and miR-98 Expression Is Altered during Transition from Normal into Cancerous State and TargetPGR,PGRMC1,CYP19A1,DDX3X, andTIMP3

“…Although the role of P4 and PGR in pathogenesis of breast cancer is controversial, in endometrial cancer, P4 deficiency has been associated with an increased risk of endometrial cancer (20,30). In ovariectomized mice, ip injection of Ishikawa cells expressing PGR-A, PGR-B, or both isoforms, only cells expressing PGR-B were found to proliferate and migrate in response to MPA treatment (20,39,42,43). As such, aberrant endometrial expression of miR-181a and miR-98 through their regulatory functions on PGR, CYP19A1, and PGRMC1 expression may play an important role in influencing the balance of E2-induced PGR and PGR-mediated genomic and nongenomic actions, specifically during transition into disease states.…”

Progesterone-Induced Cyclin G1 Inhibits the Proliferation of Endometrial Epithelial Cell and its Possible Molecular Mechanism

“…A sub-cell line stably transfected with empty vector (EV3) was used as control. These cell lines did not express estrogen receptors [15]. These cells were maintained in a complete media with neomycin (500 mg/ml, MP Biomedicals), and hygromycin (250 mg/ml, Invitrogen).…”

The Regulation and Function of the Forkhead Transcription Factor, Forkhead Box O1, Is Dependent on the Progesterone Receptor in Endometrial Carcinoma

“…Ishikawa cell lines that were stably transfected with PRA (PRA14), PRB (PRB23), or both PRA and PRB (PRAB36; L. Blok, The Netherlands) were maintained in DMEM/F12 supplemented with sodium pyruvate, penicillin/streptomycin, and 10% FBS. The parental Ishikawa cell line from which these stable PR cell lines were created did not express endogenous PRA or PRB (18).…”

“…We continued to explore the cross talk of FOXO1 and PR by determining whether progestins influenced FOXO1 protein expression in Ishikawa cell lines stably expressing PRA (PRA14), PRB (PRB23), or both PRA and PRB (PRAB36). These cell lines were generated from a parental cell line that did not express endogenous PRA or PRB (18). In response to 1 m R5020, the PRAB36 cells expressed higher levels of both nuclear and cytoplasmic FOXO1 protein (Fig.…”