Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis

Yue, Wei; Santen, Richard J.; Wang, J.-P; Li, Y; Verderame, Michael F.; Bocchinfuso, Wayne P.; Korach, Kenneth S.; Devanesan, Prabu; Todorovic, R.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1016/s0960-0760(03)00377-7

Cited by 224 publications

(181 citation statements)

References 31 publications

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“…2). The ER acts as a master regulator of gene expression in breast cancer and promotes tumor progression via upregulating genes for proliferation and cell survival while down-regulating proapoptotic and tumor-suppressing factors (3,4).…”

Section: Introductionmentioning

confidence: 99%

AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition

Shah

Mehta

Peterson

et al. 2014

Molecular Cancer Research

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Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifenresistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis.Implications: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies. Mol Cancer Res; 12(3); 394-407. Ó2013 AACR. IntroductionBreast cancer is the most common cancer in American women with an estimated 232,340 new cases of invasive and 64,640 new cases of noninvasive breast cancer this year alone. In 2013, 39,620 women were expected to die from breast cancer, and about 1 in 8 U.S. women would develop invasive breast cancer over the course of her lifetime (1). Breast cancer is frequently classified on the basis of hormone receptor status where 60% of premenopausal and 75% of postmenopausal cancers are estrogen receptor-positive (ER þ ; ref. 2). The ER acts as a master regulator of gene expression in breast cancer and promotes tumor progression via upregulating genes for proliferation and cell survival

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Section: Introductionmentioning

confidence: 99%

AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition

Shah

Mehta

Peterson

et al. 2014

Molecular Cancer Research

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“…Experiments on estrogen metabolism [6][7][8][9][10], formation of DNA adducts [11][12][13][14][15][16][17], mutagenicity [17][18][19][20][21], cell transformation [22][23][24] and carcinogenicity [25][26][27][28] have led to the hypothesis that certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, react with DNA to cause the mutations leading to the initiation of cancer ( Fig. 1) [17].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Zahid

Saeed

et al. 2007

Free Radical Biology and Medicine

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The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA forms depurinating adducts [4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua]. These adducts cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE 2 (0.2 or 0.5 μM) for 24 h at 120, 168, 216, and 264 h post-plating or one time at 1-30 μM 4-OHE 2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE 2 to E 1 (E 2 )-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3-4 fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.

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“…47,49 Concomitantly, this increased presence of proliferating cells is very sensitive to mutagens resulting in changes and potential errors in DNA replication and strand recombination. 50 Examples of specific mitogens that are responsible for both high breast density and breast cancer are insulin-like growth factor 1 and prolactin. 47,49 A mutagen of oxidative stress that has been shown to be associated with breast density and cancer is cytochrome P450 1A2 (CYP1A2).…”

Section: Breast Composition and Radiographic Appearancesmentioning

confidence: 99%

Breast composition: Measurement and clinical use

Ekpo¹,

Hogg²,

Highnam³

et al. 2015

Radiography

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Breast density is a measure of the extent of radiodense fibroglandular tissue in the breast. The risk of developing breast cancer and the risk of missing cancer at screening rise with higher breast density. In this paper, the historical background to breast density measurement is outlined and current evidence based practice is explained. The relevance of breast density knowledge to mammographic practice and image interpretation is considered in the light of clinical assessment and notification of mammographic breast density (MBD). The current work also discusses risk stratification for decisionmaking regarding screening frequency and better modalities for earlier detection of breast cancer in the dense breast. Automated volumetric approaches are explained while ultrasound, digital breast tomosynthesis, molecular breast imaging, and magnetic resonance imaging are introduced as valuable adjuncts to digital mammography for imaging the dense breast. The work concludes on the important note that screened women should be notified of their breast density, and such notification should be accompanied with clear and adequate information about breast density and cancer risk, strategies associated with lower MBD, as well as best screening intervals and pathways for women with dense breasts. Adoption of these strategies may be crucial to early detection and treatment of cancer and improving survival from the disease.

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Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis

Cited by 224 publications

References 31 publications

AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition

AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Breast composition: Measurement and clinical use

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