Role of progesterone metabolites in mammary cancer

Abstract

Among the species investigated, the rate of spontaneous cancers of mammary glands is highest in humans and dogs (Hamilton, 1974; Owen, 1979). In addition, spontaneous mammary tumours are known to occur in strains of mice (Webster & Muller, 1994), rats (Russo et al. 1990; Sukumar, 1995) and cats (Hamilton, 1974; Kessler & von Bombard, 1997). Although both oestrogen and progesterone are known to be involved in normal mammary development as well as in the proliferative changes that occur during the oestrous or menstrual cycle, pregnancy and lactation (Going et al. 1988), only the role of oestradiol has been extensively investigated. The role of progesterone in mammary cancer is not understood and, although progesterone metabolism is known to occur in mammary tissue, the potential autocrine/paracrine role of the in situ metabolites has only recently begun to be explored in human breast tissues and cell lines (Wiebe et al. 2000).

A Salicylic Acid-Based Analogue Discovered from Virtual Screening as a Potent Inhibitor of Human 20α-Hydroxysteroid Dehydrogenase

“…Progesterone is essential for the maintenance of pregnancy and its conversion to an inactive progestin, 20-hydroxyprogesterone, by AKR1C1 is associ *Address correspondence to this author at the Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia; Tel: +61 3 9903 9691; Fax: +61 3 9903 9582; E-mail: Ossama.el-kabbani@vcp.monash.edu.au ated with premature birth leading to infant morbidity and mortality [8,9]. Increased activity of AKR1C1 in the endometrium and in breast tissues leads to the formation of tumour promoting metabolites and to the development of endometriosis as well as endometrial cancer and breast cancer [10][11][12]. AKR1C1 also plays an important role in brain function where it modulates the occupancy of -aminobutyric acid type A (GABA A ) receptors through its 3 and 20 -HSD activity [13].…”

Effect of progesterone and first evidence about allopregnanolone action on the progression of epithelial human ovarian cancer cell lines

“…In breast cancer, P4 derivatives could have anti-tumor (4-pregnenes) or pro-tumor (5αpregnanes) effects [10]. P4 is converted directly into the derivatives 4-pregnanes and 5α-pregnanes like 5α-dihydroprogesterone (5α-DHP) by the irreversible action of 5α-reductase.…”

Structure-Guided Design, Synthesis, and Evaluation of Salicylic Acid-Based Inhibitors Targeting a Selectivity Pocket in the Active Site of Human 20α-Hydroxysteroid Dehydrogenase (AKR1C1)

“…While the four human HSDs belonging to the AKR1C subfamily, AKR1C1 (20α-HSD), AKR1C2 (type 3 3α-HSD), AKR1C3 (type 2 3α-HSD), and AKR1C4 (type 1 3α-HSD), share at least 86% sequence homology with AKR1C1 and AKR1C2 in particular differing only by seven residues, they display distinct positional and stereo preferences with respect to their substrates and are involved in different physiological roles. , AKR1C1 has a major role in progesterone metabolism that is essential for the maintenance of pregnancy . The conversion of progesterone to an inactive progestin, 20α-hydroxyprogesterone, by AKR1C1 is associated with premature birth leading to infant morbidity and mortality. , AKR1C1 has been implicated in brain function where it modulates the occupancy of γ-aminobutyric acid type A (GABA A ) receptors through its reductive 20α-HSD activity, which converts neuroactive steroids (3α,5α-tetrahydroprogesterone and 5α-tetrahydrodeoxycorticosterone) and their precursors (5α-dihydroprogesterone and progesterone) into inactive and ineffective 20α-hydroxysteroids, thereby removing them from the synthetic pathway. , The elimination of neuroactive steroids by AKR1C1 is implicated in symptoms of premenstrual syndrome and other neurological disorders. , The enzyme is also involved in the development of several human and rodent tumors, such as lung, endometrial, esophageal, ovarian, and breast cancers, and its overexpression in cancer cells is related to drug-resistance against several anticancer agents. − …”

“…9,11 The enzyme is also involved in the development of several human and rodent tumors, such as lung, endometrial, esophageal, ovarian, and breast cancers, and its overexpression in cancer cells is related to drug-resistance against several anticancer agents. [12][13][14][15][16] AKR1C1 is inhibited by a variety of compounds including bile acids, phytoestrogens, synthetic estrogens, benzodiazepines, nonsteroidal anti-inflammatory agents, and synthetic compounds. 10,[17][18][19][20][21] Among the inhibitors, benzbromarone and 3′,3′′,5′,5′′-tetrabromophenolphthalein are the most potent inhibitors showing IC 50 values of 48 and 33 nM, respectively.…”