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Nathan Goodyear

Circulating 2-hydroxy and 16-α hydroxy estrone levels and risk of breast canc... - 1 views

www.ncbi.nlm.nih.gov/...PMC2562592

estrogen metabolism menopause post-menopause post menopause estrogen metabolite 2-OH-estrone 16-alpha-OH-estrone 2:16alpha-OH estrone breast cancer risk hormone hormones

shared by Nathan Goodyear on 21 Aug 14 - No Cached
  • 2-OH estrogens bind to the estrogen receptor (ER) with affinity equivalent to or greater than estradiol
  • previous prospective studies have not observed any significant associations with either 2-OH or 16α-OH estrone or the ratio of the two metabolites and breast cancer risk overall.
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      whether that risk is increased or decreased
  • it has been hypothesized that metabolism favoring the 2-OH over the 16α-OH pathway may be inversely associated with breast cancer risk (28).
  • ...24 more annotations...
  • they may act as only weak mitogens (14, 15), or as inhibitors of proliferation
  • No significant associations have been observed between 2-OH estrone and breast cancer risk
  • While 16α-OH estrone binds to the ER with lower affinity than estradiol, it binds covalently (18-20) and once bound, fails to down-regulate the receptor (21). Thus, 16α-OH estrone stimulates cell proliferation in a manner comparable to estradiol in ER+ breast cancer cell lines
  • In this large prospective study of 2-OH and 16α-OH estrone metabolites and breast cancer risk, we did not observe any significant associations overall with either individual metabolite or with the ratio of the two metabolites
  • we observed positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with lower BMI and women with ER-/PR-tumors,
  • To date, several epidemiologic studies have examined the association between the 2-OH and 16α-OH estrogen metabolites and breast cancer risk with inconclusive results.
  • circulating estrogen levels have been associated more strongly with ER+/PR+ tumors than with ER-/PR- tumors
  • our results do not support the hypothesis that metabolism favoring the 2-OH estrone pathway is more beneficial to breast cancer risk than that favoring the 16α-OH estrone pathway
  • we observed significant positive associations of both 2-OH estrone and the 2:16α-OH estrone ratio with ER-/PR-tumors
  • Three (30, 32, 33) of four (30-33) studies observed RRs above 1 for the association between 16α-OH estrone and breast cancer risk (range of RRs=1.23-2.47); none of the point estimates was statistically significant though one trend was suggestive
  • based on animal studies, 2-OH estrone and the 2:16α-OH estrone ratio have been hypothesized to be inversely associated with breast cancer risk
  • No significant associations have been observed between 2-OH estrone, 16α-OH estrone, or the 2:16α-OH estrone ratio and breast cancer risk and the direction of the estimates is not consistent across studies.
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      better worded is no consistent, significant associations.   There are some studies that point to the 16 catecholestrogen and increased cancer risk; limited studies show negative effects of 2 catecholestrogens on cancer risk and prospective studies available pretty much dispel the idea that the 2:16 ratio has an risk predictability.
  • we observed a suggestive inverse association with 16α-OH estrone and a significant positive association with the 2:16α-OH estrone ratio among lean women, suggesting possible associations in a low estrogen environment.
  • 16α-OH estrone increases unscheduled DNA synthesis in mouse mammary cells (27) and hence also may be genotoxic
  • Although 2-OH estrogens are capable of redox cycling, the semiquinones and quinones (i.e., the oxidized forms) form stable DNA adducts that are reversible without DNA destruction
  • In our population of PMH nonusers, we observed no associations with ER+/PR+ tumors, but significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with ER-/PR- tumors
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      one of the few studies to find this association between 2 catecholestrogens and the 2:16 ratio and ER-/PR-tumors
  • Animal and in vitro studies have shown that hydroxy estrogens can induce DNA damage either directly, through the formation of quinones and DNA adducts, or indirectly, through redox cycling and the generation of reactive oxygen species
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      genotoxic via directe DNA adducts and indirectly via ROS; this is in addition to the proliferative effect
  • we observed a significant positive association between the 2:16α-OH estrone ratio and breast cancer risk among lean women
  • No significant associations have been observed with the 2:16α-OH estrone ratio
  • In the Danish study, no associations were observed with either ER+ or ER- tumors among PMH nonusers
  • significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio were observed among PMH users with ER+, but not ER-, tumors
  • it is possible that the genotoxicity of 2-OH estrone plays a role in hormone receptor negative tumors
  • 4-OH estrogens have a greater estrogenic potential than 2-OH estrogens, given the lower dissociation rate from estrogen receptors compared with estradiol (61), and are potentially more genotoxic since the quinones form unstable adducts, leading to depurination and mutation in vitro and in vivo
  • the balance between the catechol (i.e., 2-OH and 4-OH) and methoxy (i.e., 2-Me and 4-Me) estrogens may impact risk
  • Nathan Goodyear on 21 Aug 14
     
    The risks of estrogen metabolism are not clear cut.  Likely never will be due to the complexity of individual metabolism.  This study found no correlation between 2OH-Estrone and 2OH:16alpha-Estrone and breast cancer risk in ER+/PR+ breast cancer.  Translated: no benefit in breast cancer risk in 2OH-Estrone metabolism or increased 2OH:16alpha estrone metabolism.  There was a positive association between 2OH-Estrone and 2:16alpha-Estrone in women with ER-/PR- tumors and low BMI.
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Nathan Goodyear

Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women - 0 views

www.ncbi.nlm.nih.gov/...PMC3283536

estrogen metabolism estrogen metabolism breast cancer breast cancer

shared by Nathan Goodyear on 14 Oct 13 - No Cached
  • The ratio of the 2-hydroxylation pathway to parent estrogens was associated with a statistically significantly decreased risk of breast cancer
  • In this study, this ratio was more strongly associated with the risk of breast cancer compared with the ratio of 2-hydroxylation pathway to 16-hydroxylation pathway or unconjugated estradiol alone
  • 2-hydroxylation pathway catechols have relatively low affinities for estrogen receptors (4) and are rapidly cleared from circulation
  • ...6 more annotations...
  • In this study, the ratio of the 2-hydroxylation pathway to the 16-hydroxylation pathway was associated with a non-statistically significantly decreased risk of breast cancer
  • In this study, the ratio of catechols to methylated catechols in the 4-hydroxylation pathway was associated with statistically significantly increased risk of breast cancer.
  • This result is consistent with the hypothesis that mutagenic quinones derived from 4-hydroxylation pathway catechols contribute to pathogenesis of postmenopausal breast cancer.
  • Catechols in both the 2- and 4-hydroxylation pathways can be oxidized to form quinones; these reactive electrophiles can then react with DNA to form a variety of adducts
  • Methylation of the catechols prevents their conversion to reactive quinones
  • the most common DNA adducts derived from 4-hydroxylation pathway catechols are depurinating and highly mutagenic (7,40), most of those derived from 2-hydroxylation pathway catechols are stable and can be repaired with little error
  • Nathan Goodyear on 14 Oct 13
     
    Lower 2-OH estrone metabolism associated with lower risk of breast cancer, but 4-OH estrone associated with increased risk of breast cancer.
Nathan Goodyear

Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone rati... - 0 views

www.ncbi.nlm.nih.gov/...PMC3039007

breast cancer 2-OH-estrone 2-OH 4-OH 2:16alpha-OHE1 2:16 estrogen metabolism

shared by Nathan Goodyear on 02 Jan 13 - No Cached
  • A recent study of nine patients concluded that the urinary EMR is a good approximation for breast tissue EMR
  • A single study in young women not using oral contraceptives found fair correlation coefficients between urinary and plasma EMR
  • All of nine properly designed epidemiological studies (six prospective case-control studies and three retrospective studies) failed to show a significant relationship between urinary or circulating EMR (2OHE1/16αOHE1) and breast cancer risk
  • ...2 more annotations...
  • premenopausal studies on urinary EMR have suggested a potentially weak inverse relationship, associations were not significantly different compared with postmenopausal or overall combined studies
  • at present, there is no evidence that the EMR can predict breast cancer risk
  • Nathan Goodyear on 02 Jan 13
     
    The 2:16 OH estrone pathway is shown to not be predictive biomarker for breast cancer.
Nathan Goodyear

Urinary estrogen metabolites in women at high risk for breast cancer - 0 views

carcin.oxfordjournals.org/...1532.full

breast cancer CA estrogen metabolism 2:16 OHE 2-OH-estrone 16-alpha-OH-estrone

shared by Nathan Goodyear on 10 May 12 - No Cached
  • obesity has also been linked to preferential estrogen metabolism via the 16-alpha-hydroxylation pathway; thus, a prediction of the mechanism by which obesity could increase breast cancer risk would be through a lowering of the 2:16 ratio in favor of the 16 pathway
  • increased BMI was associated with a lower 2:16 OHE ratio
  • Our data show a significant association between alcohol use, defined as at least one drink per day or an average of seven per week, and 2:16 OHE ratio
  • ...10 more annotations...
  • An alcohol-induced rise in estrogens as a consequence of alcohol catabolism in the liver has been reported
  • The only study that looked at the association between alcohol and wine consumption in healthy women did not report a clear association
  • smoking has been reported to increase induction of the 2-hydroxylation metabolic pathway (24). However, the few epidemiological studies conducted on healthy women showed no difference in estrogen metabolites with smoking status (22) or smoking dose (20), in line with our findings.
  • Family history of a first-degree family member with breast cancer confers a 2- to 4-fold risk of developing breast cancer
  • 16% of breast cancers are due to unidentified hereditary factors
  • Estrogen metabolism occurs through enzymes whose activity is determined by the presence of specific genetic polymorphisms, thus can be defined as unique to each individual.
  • the metabolism is also influenced by a number of environmental factors, which change over a lifetime
  • significantly lower 2:16 OHE ratio in women who have known breast cancer risk factors compared with healthy women
  • There was an additional significant association specifically with BMI and alcohol use, which also supports the evidence that these factors affect estrogen metabolism
  • Profiling estrogen metabolites may identify women who are more likely to develop breast cancer within a population of women with known risk factors
  • Nathan Goodyear on 10 May 12
     
    urinary estrogen metabolites shown to provide insight into breast cancer risk.  This study suggested that a low 2:16 OHE ratio increase breast cancer risk.
Nathan Goodyear

http://joe.endocrinology-journals.org/content/167/2/281.full.pdf - 0 views

joe.endocrinology-journals.org/...281.full.pdf

estrogen metabolites 4-hydroxyestrone cancer estrogen hormones 2-hydroxyestrone 2-OH-estrone 4-OH-estrone

shared by Nathan Goodyear on 16 Jul 15 - No Cached
  • Nathan Goodyear on 16 Jul 15
     
    good discussion of the estrogen metabolites and increased estrogenic activity; including cancer risk.  Particular attention is given to the 4-hydroxyestrone metabolite.
Nathan Goodyear

Progesterone metabolites in breast cancer - 1 views

erc.endocrinology-journals.org/...717.full

progesterone metabolism tumor tumorigenesis cancer risk growth hormone hormones 5-beta-pregnanediol 5-alpha-pregnanediol 4-pregnenediol 5-alpha reductase

shared by Nathan Goodyear on 20 Feb 12 - No Cached
  • P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
  • these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
  • only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
  • ...30 more annotations...
  • P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
  • 5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
  • These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
  • Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
  • The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
  • the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
  • In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
  • The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
  • he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
  • The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
  • altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
  • In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
  • Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
  • The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
  • 3αHP inhibited whereas 5αP-stimulated proliferation
  • Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
  • Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (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 (
  • αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
  • The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
  • he effects on proliferation and adhesion were not due to P, but due to the 5α-reduced metabolites
  • The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
  • separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
  • The studies thus provided the first demonstration of the existence of specific P metabolite receptors
  • the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
  • Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
  • In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
  • The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
  • current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
  • both testosterone and DHT inhibit cell growth more or less to the same extent
  • Note that 5α-reductase reaction is not reversible
  • Nathan Goodyear on 20 Feb 12
     
    Fantastic read on the effects of progesterone metabolism on tumor and cancer growth.  Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones.  This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
Nathan Goodyear

Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women - 0 views

jnci.oxfordjournals.org/...326.full

estrogen metabolism cancer breast cancer estrogen metabolites

shared by Nathan Goodyear on 16 Jul 15 - No Cached
  • Nathan Goodyear on 16 Jul 15
     
    Get article on estrogen metabolism/metabolites and their effects on the risk of breast cancer in post menopause women.  This article brings to light new information: 2:16alpha estrone ratio is not a great predicted of risk, 2-OH and 4-OH metabolites can form quinone intermediates...
Nathan Goodyear

Hormone Therapy, Estrogen Metabolism, and Risk of Breast Cancer in the Women's Health I... - 0 views

www.ncbi.nlm.nih.gov/...PMC3493689

breast cancer estrogen metabolites 2-OH-estrone 2:16 cancer hormones estrogen

shared by Nathan Goodyear on 11 Sep 15 - No Cached
  • These results demonstrate that although 16α-OHE1 was increased more by E+P than by E-alone, the increase in the 2:16 ratio was similar for both HT regimens, due to ~4-fold greater increase in 2OHE-1 than 16α-OHE1 for both HT regimens
  • baseline and 1 year change in 16α-OHE1 showed little relationship to incident breast cancer
  • higher baseline 2-OHE1 and the 2:16 ratio were modestly associated with higher odds of incident breast cancer, but larger 1 year increase in 2-OHE-1 and the 2:16 ratio were also weakly associated with lower odds of breast cancer
  • Nathan Goodyear on 11 Sep 15
     
    Good review of the data from the WHI-HT on estrogen metabolites and breast cancer risk.  Increased 2-OHestrone and 2:16 ratio without statistical significance reached.
Nathan Goodyear

Potential Mechanisms of Estrogen Quinone Carcinogenesis - 0 views

www.ncbi.nlm.nih.gov/...PMC2556295

estrogen metabolites estrogen quinones 4-OH-estrone cancer hormones

shared by Nathan Goodyear on 19 Sep 15 - No Cached
  • 4-hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas, 2-hydroxylated metabolites were without activity
  • 4-hydroxyestradiol induced uterine tumors in 66% of CD-1 mice; whereas, mice treated with 2-hydroxyestradiol or 17β-estradiol had much lower uterine tumor incidence
  • DNA adducts of catechol estrogen quinones have been detected in the mammary glands of ACI rats treated with 4-hydroxyestradiol or it’s quinone
  • Nathan Goodyear on 19 Sep 15
     
    great read on the proposed mechanisms of how estrogen metabolites produce quinone intermediates that are carcinogenic.
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