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

Verma, U.; Kapur, M. M.; Laumas, K.R.

doi:10.1016/0022-4731(78)90124-3

Cited by 15 publications

(12 citation statements)

References 25 publications

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“…Of interest is that these pathways appear to be the same as those found in breast tissues [1]. Moreover, differences between tumorous and nontumorous breast tissue in terms of relative activities of enzymes such as 5αR and 20α-HSO [1,18,19,23] were observed between tumorigenic and nontumorigenic cell lines in the present study.…”

Section: Discussionsupporting

confidence: 56%

“…Previous in vitro metabolism studies have shown that mammary tissue from mouse [18], rat [19-21] and human [1,22,23] can convert progesterone to metabolites whose formation would require the action of the enzymes, 5αR, 3α-HSO, 3β-HSO and 20α-HSO. The results of the current investigation show that MCF-7, MDA-MB-231, T-47D and MCF-10A human breast cell lines retain the activities of these progesterone metabolizing enzymes.…”

Section: Discussionmentioning

confidence: 99%

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Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

Wiebe

Lewis

2003

BMC Cancer

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BackgroundRecent observations indicate that human tumorous breast tissue metabolizes progesterone differently than nontumorous breast tissue. Specifically, 5α-reduced metabolites (5α-pregnanes, shown to stimulate cell proliferation and detachment) are produced at a significantly higher rate in tumorous tissue, indicating increased 5α-reductase (5αR) activity. Conversely, the activities of 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO enzymes appeared to be higher in normal tissues. The elevated conversion to 5α-pregnanes occurred regardless of estrogen (ER) or progesterone (PR) receptor levels. To gain insight into these differences, the activities and expression of these progesterone converting enzymes were investigated in a nontumorigenic cell line, MCF-10A (ER- and PR-negative), and the three tumorigenic cell lines, MDA-MB-231 (ER- and PR-negative), MCF-7 and T-47D (ER- and PR-positive).MethodsFor the enzyme activity studies, either whole cells were incubated with [14C]progesterone for 2, 4, 8, and 24 hours, or the microsomal/cytosolic fraction was incubated for 15–60 minutes with [3H]progesterone, and the metabolites were identified and quantified. Semi-quantitative RT-PCR was employed to determine the relative levels of expression of 5αR type1 (SRD5A1), 5αR type 2 (SRD5A2), 20α-HSO (AKR1C1), 3α-HSO type 2 (AKR1C3), 3α-HSO type 3 (AKR1C2) and 3β-HSO (HSD3B1/HSD3B2) in the four cell lines using 18S rRNA as an internal control.ResultsThe relative 5α-reductase activity, when considered as a ratio of 5α-pregnanes/4-pregnenes, was 4.21 (± 0.49) for MCF-7 cells, 6.24 (± 1.14) for MDA-MB-231 cells, 4.62 (± 0.43) for T-47D cells and 0.65 (± 0.07) for MCF-10A cells, constituting approximately 6.5-fold, 9.6-fold and 7.1 fold higher conversion to 5α-pregnanes in the tumorigenic cells, respectively, than in the nontumorigenic MCF-10A cells. Conversely, the 20α-HSO and 3α-HSO activities were significantly higher (p < 0.001) in MCF-10A cells than in the other three cell types. In the MCF-10A cells, 20α-HSO activity was 8-14-fold higher and the 3α-HSO activity was 2.5-5.4-fold higher than in the other three cell types. The values of 5αR:20α-HSO ratios were 16.9 – 32.6-fold greater and the 5αR:3α-HSO ratios were 5.2 – 10.5-fold greater in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. RT-PCR showed significantly higher expression of 5αR1 (p < 0.001), and lower expression of 20α-HSO (p < 0.001), 3α-HSO2 (p < 0.001), 3α-HSO3 (p < 0.001) in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells.ConclusionThe findings provide the first evidence that the 5αR activity (leading to the conversion of progesterone to the cancer promoting 5α-pregnanes) is significantly higher in the tumorigenic MCF-7, MDA-MB-231 and T-47D breast cell lines than in the nontumorigenic MCF-10A cell line. The higher 5αR activity coincides with significantly greater expression of 5αR1. On the other hand, the activities of 20α-HSO and 3α-HSO are higher in the MCF-10A cells than in MCF-7, MDA-MB-231 and T-47D cells; these differences in act...

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

Wiebe

Lewis

2003

BMC Cancer

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“…RIA of LH, FSH, prolactin, estradiol, cortisol and determination of estrogen and progesterone receptor levels in the malignant breast tissues were carried out in the Department of Reproductive Biology, AIIMS, according to the methods established in this department Orba et al, 1978;Singb et al, 1978;Verma et al, 1978).…”

Section: Methodsmentioning

confidence: 99%

Urinary melatonin levels in human breast cancer patients

Bartsch

Jain

et al. 1981

J. Neural Transmission

113

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Urinary melatonin levels were measured in 10 postmenopausal Indian women suffering from advanced stages of breast cancer and in 9 well-matched women with non-endocrine complaints, mostly uterovaginal prolapse. Urines of each patient were collected over a period of 2-3 days in four 4-hourly intervals from 6 a.m. to 10 p.m. and one 8-hourly interval from 10 p.m. to 6 a.m. Serum LH, FSH, prolactin, estradiol and cortisol levels at 11 a.m. were determined as well as estrogen and progesterone receptors of the breast tumors. It was found that 24 hour urinary melatonin excretion in cancer patients was on the average 31% decreased as compared to the controls. This change was accompanied by a 33% increase in serum cortisol levels in the cancer patients. The melatonin excretion patterns of the cancer patients were not synchronized as compared to synchronized patterns of the controls. The number of tumors tested for steroid receptors does not yet allow to conclude if melatonin is different in patients with or without hormone-dependent tumors. The data suggest that pineal melatonin secretion may be modified in quantity as well as rhythmicity in breast cancer patients.

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“…In the mammary gland 20a-hydroxypregn-4-en-3-one was the major metabolite. Although the formation of this metabolite has previously been reported in the mammary gland of rat (Lawson & Pearlman, 1964), rabbit (Chatterton, Chatterton & Hellman, 1969) and man (Verma, Kapur & Laumas, 1978) the physiological significance of its formation is not clear. Further work on the interaction of the metabolites of progesterone with the nuclear and cytoplasmic progesterone receptors in different tissues may clarify their functional role in the mechanism of action of progesterone at the molecular level.…”

Section: Discussionmentioning

confidence: 93%

Fate of Progesterone in the Plasma and Various Tissues of Anaesthetized Rabbits

Verma¹,

Laumas²

1981

Journal of Endocrinology

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Studies on the metabolism of progesterone in rabbit plasma and tissues during constant infusion of [3H]progesterone revealed a gradual increase in the concentration of progesterone in plasma until a state of equilibrium was attained about 2 h after the start of infusion. The metabolic clearance rate of progesterone was 0.116 l/min and the turn-over time was 0.006 min/ml plasma. Under conditions of equilibrium, the concentration of radioactivity as well as that of labelled progesterone was higher in the tissues than in plasma. On a unit-weight basis, myometrium localized 6.6 nCi, Fallopian tube 5.5 nCi and vagina 6.1 nCi [3H]progesterone/g tissue. A higher concentration of progesterone, 16.5 nCi, was localized in the mammary gland tissue. Skin localized only 0.9 nCi progesterone and the lowest amount (0.34 nCi/ml) was found in plasma. The metabolism of progesterone in tissues differed from that in plasma. In plasma only 5.6% of the infused steroid was recovered as unconverted progesterone and the major amount was metabolized to polar compounds with smaller amounts of 5 alpha-pregnane-3,20-dione, 5 alpha-pregnan-3 beta-ol-20-one and 20 alpha hydroxypregn-4-en-3-one. In the myometrium and Fallopian tubes the major metabolites were 5 alpha-pregnan-3 beta-ol-20-one and 5 alpha-pregnane-3,20-dione respectively. In the vagina, like the myometrium, 5 alpha-pregnan-3 beta-ol,20-one was the major metabolite. 20 alpha-Hydroxypregn-4-en-3-one was the major identified metabolite of mammary gland tissue.

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

Cited by 15 publications

References 25 publications

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

Urinary melatonin levels in human breast cancer patients

Fate of Progesterone in the Plasma and Various Tissues of Anaesthetized Rabbits

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