Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed by the 5α-reductase inhibitor, finasteride

WIEBE J; RIVAS MA; MERCOGLIANO MF; ELIZALDE PV; SCHILLACI R

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2015 vol. 149 p. 27 - 34

0960-0760

Progesterone has long been linked to breast cancer but its actual role as a cancer promoter has remained in dispute. Previous in vitro studies have shown that progesterone is converted to 5α-dihydroprogesterone (5αP) in breast tissue and human breast cell lines by the action of 5α-reductase, and that 5αP acts as a cancer-promoter hormone. Also studies with human breast cell lines in which the conversion of progesterone to 5αP is blocked by a 5α-reductase inhibitor, have shown that the in vitro stimulation in cell proliferation with progesterone treatments are not due to progesterone itself but to the metabolite 5αP. No similar in vivo study has been previously reported. The objective of the current studies was to determine in an in vivo mouse model if the presumptive progesterone-induced mammary tumorigenesis is due to the progesterone metabolite, 5αP. BALB/c mice were challenged with C4HD murine mammary cells, which have been shown to form tumors when treated with progesterone or the progestin, medroxyprogesterone acetate. Cells and mice were treated with various doses and combinations of progesterone, 5αP and/or the 5α-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. Proliferation of C4HD cells and induction and growth of tumors was stimulated by treatment with either progesterone or 5αP. The progesterone-induced stimulation was blocked by finasteride and reinstated by concomitant treatment with 5αP. The 5αP-induced tumors expressed high levels of ER, PR and ErbB-2. Hormone measurements showed significantly higher levels of 5αP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5αP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. The results indicate that the stimulation of C4HD tumor growth in BALB/c mice treated with progesterone is due to the progesterone metabolite 5αP formed at elevated levels in mammary cells as a result of the 5α-reductase action on progesterone. The results provide the first in vivo demonstration that stimulation of breast cell tumorigenesis and tumor growth accompanying progesterone treatment is due to the progesterone metabolite 5αP, and that breast tumorigenesis can be blocked with the 5α-reductase inhibitor, finasteride.