Characterization of progesterone receptors and metabolism of progesterone in the normal and cancerous human mammary gland

Abstract

The molecular interaction of progesterone was investigated in 18 cancerous and 12 normal human mammary gland tissues. The time course analysis of progesterone localization showed that it was initially concentrated in the cytosol and subsequently transferred to the nucleus. In the cancerous tissue the nuclear fraction had significantly higher amount of the steroid than in the cytosol fraction while in the normal mammary gland tissue localization of progesterone in the nuclear fraction was only slightly higher compared with the cytosolic fraction. Both in the normal and cancerous mammary tissue, progesterone was bound to a 4.3S receptor but a characteristic 6.7S binding component was noted in the normal mammary tissue. The number of specific binding sites in the normal and cancerous cytosol was of the order of 2.1 and 1.5 pmol/mg protein and the dissociation constant was 0.42 × 10−9M−1 and 0.98 × 10−9M−1 respectively. The binding component was a thermolabile protein but different than plasma proteins. Ligand specificity studies revealed that along with progesterone, other progestins compete for the binding sites. In the mammary gland, progesterone was metabolised mainly to 20-hydroxy-4-pregnen-3-one, 5α-pregnane-3,20-dione and polar compounds. The breast carcinoma tissue showed higher metabolism than the normal breast tissue. In the breast carcinoma 20β-hydroxy-4-pregnen-3-one was the major metabolite whereas in the normal mammary gland 20α-hydroxy-4-pregnen-3-one was the major metabolite