TY - JOUR
T1 - Progesterone regulates catechol-O-methyl transferase gene expression in breast cancer cells
T2 - Distinct effect of progesterone receptor isoforms
AU - Salama, Salama A.
AU - Jamaluddin, Mohammad
AU - Kumar, Raj
AU - Hassan, Memy H.
AU - Al-Hendy, Ayman
N1 - Funding Information:
This work was supported by UTMB NIEHS Center Pilot Project #E506676 to S.A. Salama.
PY - 2007/11
Y1 - 2007/11
N2 - There is strong evidence that catechol-O-methyl transferase (COMT) protects breast cells against estrogen-induced cancer by detoxifying catecholestrogens, the carcinogenic estrogen metabolites. COMT gene expression is controlled by two promoters - a proximal promoter (COMTP1) and a distal promoter (COMTP2) - that regulate the expression of soluble (S-COMT) and membrane-bound (MB-COMT) isoforms, respectively. We investigated the transcriptional regulation of the COMT gene by progesterone/progesterone receptors in breast cancer cells. Our results indicated that progesterone (P4) downregulates COMT gene expression in breast cancer cell lines. In addition, the COMTP1 and COMTP2 harbor several progesterone response elements (PREs). Electrophoretic mobility shift assay (EMSA) indicated that nuclear extracts of T47D cells bind to the identified PREs in COMTP1. Site-directed mutagenesis of PREs in COMTP1 not only reversed the P4-induced inhibition of COMTP1, but also increased its basal activity. The two progesterone receptor isoforms, PR-A and PR-B, were found to have opposite effects on the regulation of P4 in COMT expression; PR-A is associated with P4-induced upregulation of COMT, while PR-B is associated with P4-induced downregulation of COMT. In summary, our data demonstrated that P4 downregulates the COMT gene expression through multiple PREs in the COMT promoters and that different progesterone receptor isoforms have distinctive effects on COMT gene expression.
AB - There is strong evidence that catechol-O-methyl transferase (COMT) protects breast cells against estrogen-induced cancer by detoxifying catecholestrogens, the carcinogenic estrogen metabolites. COMT gene expression is controlled by two promoters - a proximal promoter (COMTP1) and a distal promoter (COMTP2) - that regulate the expression of soluble (S-COMT) and membrane-bound (MB-COMT) isoforms, respectively. We investigated the transcriptional regulation of the COMT gene by progesterone/progesterone receptors in breast cancer cells. Our results indicated that progesterone (P4) downregulates COMT gene expression in breast cancer cell lines. In addition, the COMTP1 and COMTP2 harbor several progesterone response elements (PREs). Electrophoretic mobility shift assay (EMSA) indicated that nuclear extracts of T47D cells bind to the identified PREs in COMTP1. Site-directed mutagenesis of PREs in COMTP1 not only reversed the P4-induced inhibition of COMTP1, but also increased its basal activity. The two progesterone receptor isoforms, PR-A and PR-B, were found to have opposite effects on the regulation of P4 in COMT expression; PR-A is associated with P4-induced upregulation of COMT, while PR-B is associated with P4-induced downregulation of COMT. In summary, our data demonstrated that P4 downregulates the COMT gene expression through multiple PREs in the COMT promoters and that different progesterone receptor isoforms have distinctive effects on COMT gene expression.
KW - Breast cancer
KW - COMT
KW - Estrogen metabolism
KW - Progesterone
KW - Progesterone receptor isoforms
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U2 - 10.1016/j.jsbmb.2007.03.049
DO - 10.1016/j.jsbmb.2007.03.049
M3 - Article
C2 - 17689241
AN - SCOPUS:34548477436
SN - 0960-0760
VL - 107
SP - 253
EP - 261
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3-5
ER -