Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma

Lewis, Michael J.; Wiebe, John P.; Heathcote, J. G.

doi:10.1186/1471-2407-4-27

Cited by 114 publications

(92 citation statements)

References 43 publications

(64 reference statements)

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“…Thus, AKR1C2 and possibly AKR1C1 may indirectly regulate the activity of the androgen receptor by promoting catabolism of DHT within prostatic cells, thereby modulating intracellular DHT levels. A similar finding was also observed in human breast cancer in which selective loss of AKR1C1, which reduces progesterone to the weak progestin 20␣-dihydroxyprogestgerone, was found in tumors compared with paired unaffected tissues (Ji et al, 2004;Lewis et al, 2004). Similar to prostate cancer, we predict that reduced AKR1C1 expression would also hinder progesterone metabolism, thereby augmenting the activity of the progesterone receptor (Ji et al, 2004).…”

supporting

confidence: 61%

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Lou

Du²,

Ji³

et al. 2006

Mol Pharmacol

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AKR1C2, also referred to as the human bile acid binder and 3␣-hydroxysteroid dehydrogenase type III, is a multifunctional oxidoreductase able to stereoselectively reduce steroids as well as oxidize or reduce polyaromatic hydrocarbons. Previously, this same protein was also identified by its robust induction by phase II inducers in HT29 cells. In HepG2 cells, both AKR1C2 and AKR1C1 (97% sequence homology) were induced by phase II inducers but not the highly related AKR1C3 and AKR1C4 family members (84% sequence homology). We now report the initial characterization of the proximal promoter of AKR1C2 in HepG2 cell line and the identification of a potent enhancer-like element responsive to phase II inducers located approximately 5.5 kilobases upstream from the transcription start site. DNA sequence analysis of this enhancer element revealed that it contained a consensus antioxidant response element (ARE), which was confirmed by mutation analysis.Treatment with phase II inducers leads to increased accumulation of nuclear factor-erythroid 2 p45-related factor (NRF) 2 in the nucleus, which was associated with increased binding to this ARE as determined by electrophoretic mobility shift assay. Transient transfection with Nrf2 increased the transcriptional activity of the ARE of AKR1C2 comparable with that observed with phase II inducers. Chromatin immunoprecipitation (ChIP) analysis also confirmed increased NRF2 binding to the ARE after induction by a phase II inducer. The AKR1C1 promoter also harbored this same ARE element in a highly homologous region, which was also bound by NRF2 in a ChiP analysis. No induction of the ARE of AKR1C2 was detected in Nrf2fibroblasts. The regulation of AKR1C2 by this distal ARE suggests that AKR1C2 detoxifies products of reactive oxidant injury, which has important implications for both hormone and xenobiotic metabolism.

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supporting

confidence: 61%

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Lou

Du²,

Ji³

et al. 2006

Mol Pharmacol

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“…RT-PCR analyses on tissues from 38 patients showed significantly higher levels of expression of 5a-reductase type 1 (SRD5A1) and 5a-reductase type 2 (SRD5A2) mRNA and significantly lower levels of expression of the 3a-HSO type 2 (AKR1C3), 3a-HSO type 3 (AKR1C2) and 20a-HSO (AKR1C1) mRNAs in the tumor tissues than in the normal tissues (Lewis et al 2004) (Fig. 4a).…”

Section: Changes In Expression Of Progesteronemetabolizing Enzymesmentioning

confidence: 99%

“…This is in marked contrast to the actions of P metabolites, where the 5a-pregnanes stimulate and the 4-pregnenes inhibit cell proliferation. Also, 5a-reductase type 2 (SRD5A2), which catalyzes J P Wiebe: Progesterone metabolites in breast cancer www.endocrinology-journals.org reduction of testosterone to DHT in androgendependent tissues such as the prostate, is present in very low levels in breast tissue (Ji et al 2004, Lewis et al 2004 and human breast cancer cell lines (Wiebe & Lewis 2003). In breast tissue, 5a-reductase type 1 (SRD5A1) is predominant and it may be that P is a better substrate than testosterone for this isoenzyme.…”

Section: Implications Of Changes In Progesterone 5a-reductase Activitmentioning

confidence: 99%

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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“…Of the three known isoforms, 5aR1 is expressed more frequently in the breast than 5aR2 and is considered the principal isoform (Suzuki et al 2001) despite its lower affinity for testosterone (Jin & Penning 2006), while 5aR3 has not been reported in the breast. The importance of 5aR1 in breast cancer development remains unclear, as either higher (Lewis et al 2004) or lower (Zhao et al 2010) levels of 5aR1 have been reported in tumour compared with matched normal tissues. However, a large number of studies suggest an inhibitory role for 5aR1 in disease progression.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Complexities of androgen receptor signalling in breast cancer

McNamara¹,

Moore²,

Hickey³

et al. 2014

Endocrine-Related Cancer

123

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While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.

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Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma

Cited by 114 publications

References 43 publications

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Progesterone metabolites in breast cancer

Complexities of androgen receptor signalling in breast cancer

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