The role of progesterone metabolites in breast cancer: Potential for new diagnostics and therapeutics

Wiebe, John P.; Lewis, Michael J.; Cialacu, V.; Pawlak, Kevin J.; Zhang, G.

doi:10.1016/j.jsbmb.2004.12.003

Cited by 34 publications

(46 citation statements)

References 18 publications

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“…5b). Similar effects have also been demonstrated recently in MCF-10A, T47D, and MDA-MB-231 cells , Pawlak et al 2005. The opposing actions of 5aP and 3aHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5a-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.…”

Section: Effects Of Progesterone Metabolites On Cell Adhesionsupporting

confidence: 85%

“…Data from studies in which cells were treated simultaneously with both 3aHP and 5aP show that the independent effects of the individual hormones on proliferation and adhesion are cancelled out when present in equal concentrations (Fig. 5c) (Pawlak et al 2005) and support the view that the overall effects may depend on the relative concentration of each in the milieu.…”

Section: Proof Of Principlesupporting

confidence: 52%

“…Stimulation in cell numbers was also observed when cells were treated with other 5a-pregnanes, such as 5a-pregnan-3a-ol-20-one, 5a-pregnan-20a-ol-3-one, and 5a-pregnane-3a,20a-diol, whereas other 4-pregnenes such as 20a-HP and 4-pregnene-3a,20a-diol resulted in suppression of cell proliferation similar to that of 3aHP . Stimulation of cell proliferation with 5aP and inhibition with 3aHP were also observed in all other breast cell lines examined, whether ER/Pnegative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (MCF-10A) , Pawlak et al 2005, G Zhang & J P Wiebe, unpublished results). Increases in cell numbers can result not only from increased rates of cell division, but also from decreases in rate of cell attrition via programmed cell death (apoptosis) (Thompson 1995).…”

Section: Effects Of Progesterone Metabolites On Cell Proliferation Mmentioning

confidence: 73%

See 2 more Smart Citations

Progesterone metabolites in breast cancer

Wiebe¹

2006

Endocr Relat Cancer

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In the 70 years since progesterone (P) was identified in corpus luteum extracts, its metabolism has been examined extensively in many tissues and cell lines from numerous species. In addition to the reproductive tissues and adrenals, every other tissue that has been investigated appears to have one or more P-metabolizing enzyme, each of which is specific for a particular site on the P molecule. In the past, the actions of the P metabolizing enzymes generally have been equated to a means of reducing the P concentration in the tissue microenvironment, and the products have been dismissed as inactive waste metabolites. In human breast tissues and cell lines, the following P-metabolizing enzymes have been identified: 5a-reductase, 3a-hydroxysteroid oxidoreductase (3a-HSO), 3b-HSO, 20a-HSO, and 6a-hydroxylase. Rather than providing diverse pathways for inactivating and controlling the concentration of P in breast tissue microenvironments, it is proposed that the enzymes act directly on P to produce two types of autocrines/paracrines with opposing regulatory roles in breast cancer. Evidence is reviewed which shows that P is directly converted to the 4-pregnenes, 3a-hydroxy-4-pregnen-20-one (3a-dihydroprogesterone; 3aHP) and 20a-dihydro-progesterone (20aHP), by the actions of 3a-HSO and 20a-HSO respectively and to the 5a-pregnane, 5a-pregnane-3,20-dione(5a-dihydroprogesterone; 5aP), by the irreversible action of 5a-reductase. In vitro studies on a number of breast cell lines indicate that 3aHP promotes normalcy by downregulating cell proliferation and detachment, whereas 5aP promotes mitogenesis and metastasis by stimulating cell proliferation and detachment. The hormones bind to novel, separate, and specific plasma membrane-based receptors and influence opposing actions on mitosis, apoptosis, and cytoskeletal and adhesion plaque molecules via cell signaling pathways. In normal tissue, the ratio of 4-pregnenes:5a-pregnanes is high because of high P 3a-and 20a-HSO activities/expression and low P 5a-reductase activity/expression. In breast tumor tissue and tumorigenic cell lines, the ratio is reversed in favor of the 5a-pregnanes because of altered P-metabolizing enzyme activities/expression. The evidence suggests that the promotion of breast cancer is related to changes in in situ concentrations of cancerinhibiting and -promoting P metabolites. Current estrogen-based theories and therapies apply to only a fraction of all breast cancers; the majority (about two-thirds) of breast cancer cases are estrogeninsensitive and have lacked endocrine explanations. As the P metabolites, 5aP and 3aHP, have been shown to act with equal efficacy on all breast cell lines tested, regardless of their tumorigenicity, estrogen sensitivity, and estrogen receptor/progesterone receptor status, it is proposed that they offer a new hormonal basis for all forms of breast cancer. New diagnostic and therapeutic possibilities for breast cancer progression, control, regression, and prevention are suggested.

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Section: Effects Of Progesterone Metabolites On Cell Adhesionsupporting

confidence: 85%

Section: Proof Of Principlesupporting

confidence: 52%

Section: Effects Of Progesterone Metabolites On Cell Proliferation Mmentioning

confidence: 73%

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Progesterone metabolites in breast cancer

Wiebe¹

2006

Endocr Relat Cancer

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“…There may be substantive metabolic differences between native and synthetic forms of P4 that could account for some of the conflicting clinical trial outcomes. The metabolism of natural P4 in normal breast tissue generates products that have anticarcinogenic activities (19), but there is also a risk that chronic dosing with low-dose P4-implanted pellets can stimulate growth of breast cancer tumor cells implanted into nude mice (12). Moreover, natural P4 and MPA have different target genes in breast cancer cell lines, as evidenced by a cDNA microarray study of 3,000 genes (20).…”

Section: Introductionmentioning

confidence: 99%

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

Atif

Sayeed

Yousuf

et al. 2011

Mol Med

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“…20a-HSD probably plays a role in regulating the amount of progesterone and in protecting against its toxic effect. Recently, the ratio of 5a-pregnanes produced by 5a-reductase to 4-pregnenes produced by 20a-HSD or 3a-HSD from progesterone has been demonstrated to provide a hormonal basis for breast cancer [6,7]. Thus, the inhibition of 20a-HSD by environmental pollutants and xenobiotic compounds can increase this ratio and may promote breast cancer by stimulating cell proliferation and detachment.…”

mentioning

confidence: 99%

Inhibitory effects of diesel exhaust components and flavonoids on 20α-hydroxysteroid dehydrogenase activity in mouse tissues

Shimada

Ohtaguro

Miura

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of diesel exhaust components and flavonoids on 20a-hydroxysteroid dehydrogenase (20a-HSD) activity were examined in cytosolic fractions from the liver, kidney and lung of male mice. 9,10-Phenanthrenequinone (9,10-PQ) and 1,2-naphthoquinone (1,2-NQ), which are contained in diesel exhaust particles (DEPs), potently inhibited 20a-HSD activity in liver cytosol. 9,10-PQ also inhibited the enzyme activity in lung cytosol. However, 20a-HSD activity in kidney cytosol was little inhibited by 9,10-PQ or 1,2-NQ. Flavonoids such as quercetin, fisetin and kaempferol exhibited high inhibitory potencies for 20a-HSD activity in liver cytosol, whereas these flavonoids were poor inhibitors for the enzyme activity in kidney cytosol. It is likely that several diesel exhaust components and flavonoids augment the signaling of progesterone in the liver cells, by potently inhibiting 20a-HSD activity in mouse liver cytosol. The possibility that there are distinct enzymes catalyzing 20a-HSD activity in the non-reproductive tissues of male mice is also discussed.

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The role of progesterone metabolites in breast cancer: Potential for new diagnostics and therapeutics

Cited by 34 publications

References 18 publications

Progesterone metabolites in breast cancer

Progesterone metabolites in breast cancer

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

Inhibitory effects of diesel exhaust components and flavonoids on 20α-hydroxysteroid dehydrogenase activity in mouse tissues

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