Progesterone Receptor (PR) Isoforms PRA and PRB Differentially Regulate Expression of the Breast Cancer Resistance Protein in Human Placental Choriocarcinoma BeWo Cells

Abstract

Breast cancer resistance protein (BCRP) plays a significant role in drug disposition and in conferring multidrug resistance in cancer cells. Previous studies have shown that steroid hormones such as 17␤-estradiol and progesterone can affect BCRP expression in cancer cells. In this study, we investigated the molecular mechanism by which BCRP expression in human placental choriocarcinoma BeWo cells is regulated by progesterone. Transfection of the progesterone receptor (PR) isoforms PRA and PRB resulted in a similarly increased expression of PRA and PRB, respectively. However, progesterone significantly increased BCRP expression and activity only in PRBtransfected cells. This stimulatory effect of progesterone was abrogated by the PR antagonist mifepristone (RU-486). Consistently, transcriptional activity of the BCRP promoter was induced 2-to 6-fold by 10 Ϫ8 to 10 Ϫ5 M progesterone in PRBtransfected cells. Progesterone had little effect on BCRP expression and activity and transcriptional activity of the BCRP promoter in PRA-transfected cells; however, cotransfection of PRA and PRB significantly decreased the progesterone-response compared with that in cells transfected with only PRB. Mutations in a novel progesterone response element (PRE) identified between Ϫ243 to Ϫ115 bp of the BCRP promoter region significantly attenuated the progesterone-response in PRB-transfected cells, and deletion of the PRE nearly completely abrogated the progesterone effect. Specific binding of both PRA and PRB to the BCRP promoter through the identified PRE was confirmed using the electrophoretic mobility shift assay. Collectively, progesterone induces BCRP expression in BeWo cells via PRB but not PRA. PRA represses the PRB activity. Thus, PRA and PRB differentially regulate BCRP expression in BeWo cells.

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…The promoter of ABCG2 has been reported to contain an overlapping estrogen response element and a progesterone response element, which were shown to specifically bind ERα and progesterone receptor A and B (PRA and PRB), respectively. Expression of ABCG2 was reported to be induced by estrogen through ERα; however, enhanced expression of ABCG2 by progesterone was observed only in model cells expressing PRB, whereas PRA was shown to repress PRB activity (Ee et al, 2004;Wang et al, 2008).…”

Emodin As an Effective Agent in Targeting Cancer Stem-Like Side Population Cells of Gallbladder Carcinoma

“…Although the molecular mechanisms regulating the expression of ABCG2 remain unclear, many agents have been found to regulate the expression of ABCG2, such as human placental lactogen, human prolactin, and folate [42][43][44]. Yin et al found that transforming growth factor-beta decreased ABCG2 gene expression in SP cells from MCF-7 [27].…”

Multidrug Resistence and Breast Cancer

“…Wang et al found there were progesterone response elements on the upstream of BCRP promoter [114] and they note that the identified PRE is exactly the same as the estrogen response element published by Ee et al [117]. They found that PRB is a strong activator of transcription of the BCRP promoter, and PRA represses the PRB activity in the human placental choriocarcinoma BeWo cells.…”

“…PR expression in breast cancer is also an important indicator of likely responsiveness to endocrine agents. It has been shown that PRA and PRB are expressed in similar amounts in most breast tumors [114]. Some data indicated that progesterone via PRs may be related to the regulation of MDR in breast cancer.…”