Progesterone regulates catechol-O-methyl transferase gene expression in breast cancer cells

Distinct effect of progesterone receptor isoforms

Salama A. Salama, Mohammad Jamaluddin, Raj Kumar, Memy H. Hassan, Ayman Al-Hendy

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)253-261
Number of pages9
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume107
Issue number3-5
DOIs
StatePublished - Nov 2007

Fingerprint

Guaiacol
Progesterone Receptors
Transferases
Gene expression
Progesterone
Protein Isoforms
Cells
Breast Neoplasms
Gene Expression
Response Elements
Down-Regulation
catechol
Estrogens
Catechol Estrogens
Electrophoretic mobility
Mutagenesis
Electrophoretic Mobility Shift Assay
Metabolites
Ports and harbors
Site-Directed Mutagenesis

Keywords

  • Breast cancer
  • COMT
  • Estrogen metabolism
  • Progesterone
  • Progesterone receptor isoforms

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Progesterone regulates catechol-O-methyl transferase gene expression in breast cancer cells : Distinct effect of progesterone receptor isoforms. / Salama, Salama A.; Jamaluddin, Mohammad; Kumar, Raj; Hassan, Memy H.; Al-Hendy, Ayman.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 107, No. 3-5, 11.2007, p. 253-261.

Research output: Contribution to journalArticle

Salama, Salama A. ; Jamaluddin, Mohammad ; Kumar, Raj ; Hassan, Memy H. ; Al-Hendy, Ayman. / Progesterone regulates catechol-O-methyl transferase gene expression in breast cancer cells : Distinct effect of progesterone receptor isoforms. In: Journal of Steroid Biochemistry and Molecular Biology. 2007 ; Vol. 107, No. 3-5. pp. 253-261.
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