Progesterone receptor induction by danazol in cultured cancer cells and the rat uterus.
We have previously reported that clinical trials relating to the use of danazol in the management of benign breast disease show a positive correlation between favourable clinical response and an induction of progesterone receptors in the affected tissue which is maintained for a period of at least 6 months subsequent to the cessation of treatment. Further studies designed at elucidating more clearly the actions of danazol at the cellular and molecular levels have confirmed that progesterone receptors are down-regulated by short-term progestin action at the level of the mRNA transcript, but that danazol is subsequently able to produce an enhanced cellular response, inducing progesterone receptors in the presence of oestrogenic agents. Uteri from danazol-treated rats showed a doubling of progesterone receptor concentrations compared with the control uteri. In the mammary cancer cell line T-47D, cells treated with danazol had increased progesterone receptor concentrations of 558.4 +/- 32.0 compared with 152.6 +/- 7.0 fmol/mg protein in the control cells. In both cases, these inductions were observed following a period of progesterone receptor suppression. Short-term molecular studies on T-47D cells indicated that progesterone and danazol initially inhibit mRNA transcription, but that 24 h after treatment an induction is observed. This is especially marked in the danazol-treated cells.
Gledhill
J M
JM
Department of Biochemistry, Faculty of Basic Medical Sciences, Queen Mary and Westfield College, London, England.
Barker
S
S
Wanless
C
C
Hinson
J P
JP
Puddefoot
J R
JR
Panahy
C
C
Goode
A W
AW
Vinson
G P
GP
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D003613:Danazol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004971:Estrus; D005003:Ethisterone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000378:metabolism*
D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D003613:Danazol; D005003:Ethisterone