Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention – A review

Abstract

Studies in hamsters, mice and rats have demonstrated that estradiol (E2), its interconvertible metabolite estrone (E1) and their catechol metabolites, in particular 4-hydroxy E2/E1, are carcinogenic in the kidney, uterus and mammary gland. Observational studies and clinical trials consistently show that sustained exposure to E2/E1 is associated with the development of sporadic breast cancer. The weight of evidence supports the contribution of two complementary pathways in the initiation, promotion and progression of breast cancer. One pathway involves activation of nuclear and cytoplasmic signaling pathways through the binding of estrogen to nuclear and membrane-bound estrogen receptors leading to increased cell proliferation. The other pathway involves the oxidative metabolism of E2/E1 to catechols and then reactive quinones that can contribute to oxidative DNA damage and form specific, mutagenic depurinating adducts with adenine and guanine which then in turn can serve as biomarkers for the occurrence of these processes. Both pathways can serve as portals to preventive intervention. Antiestrogens are used clinically to block receptor-mediated signaling to block tumor growth. Various chemopreventive agents such as sulforaphane (SFN) and resveratrol have been shown in cell culture to block oxidative metabolism of E2/E1 and thus prevent DNA damage. Pretreatment of MCF-7 and MCF-10F cells with and inhibitor of catechol-O-methyltransferase (COMT) followed by treatment with E2 or 4-OH E2 caused increased oxidative DNA damage (8-oxo-dG) and depurinating DNA adducts showing the importance of E2-catechol O-methylation by COMT as a protective pathway. E2 Treatment of MCF-10A cells with E2 or 4-OH E2 caused an increase in E2-adenine and guanine adducts. Treatment with sulforaphane increased NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase A1 (GSTA1) expression without affecting expression of catechol-O-methyltransferase (COMT) or cytochrome P450 1B1. Pretreatment with SFN decreased depurinating DNA adducts while increasing levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates. Treatment of MCF-10F cells with E2 or 4-OH-E2 also caused increased depurinating DNA adducts and neoplastic transformation while pretreatment with resveratrol caused a reduction in adduct levels and neoplastic transformation. Increased levels of estrogen-quinone conjugates and DNA adducts have also been detected in urine of women at increased risk for and with breast cancer. These observations support the notion that targeting the estrogen/estrone metabolism pathway may be another way to reduce breast cancer risk.

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

“…Oestrogen has also been suggested to give rise to cancer-initiating mutations through the formation of DNA adducts and other oxidative lesions, high levels of which have been observed in women with breast, thyroid or ovarian cancer (68). On the other hand, MSH6 is increasingly being implicated in such oestrogen-associated cancers as 1) in vitro oestrogen exposure after catechol-O-methyltransferase inhibition increases the levels of 8-oxo-dG (69), an oxidative DNA lesion whose repair involves the MutSα complex; 2) MSH6 mutations and reduced MSH6 mRNA expression have been reported in breast cancer patients and breast tumour derived cell lines, respectively (70); 3) in LS patients, endometrial cancer is commonly associated with MSH6 mutations (27,31,39,62); 4) MSH2-the binding partner of MSH6 in MutSα-is able to transactivate the oestrogen receptor α, through its MSH6 interaction domain (71); 5) several DNA repair SNPs have been associated with increased oestrogen sensitivity in the development of breast cancer (72)(73)(74). Also, we previously reported a non-significant breast cancer risk increase in rs1042821 variant allele homozygotes (53), in line with the results reported here.…”

Az ösztrogénmetabolom biológiai és klinikai jelentősége lokális folyamatokban

“…Az ekvileninösztrogé-neket tartalmazó készítményekben található ekvilenin reaktívkatechol-metabolitja a 4-hidroxi-ekvilenin, amely gátolja a detoxifikáló enzimek, például a GST vagy a COMT működését, így az ösztrogénmetabolizmust is befolyásolja [19,20,24].…”

Human Tissue Investigations Using PALS Technique - Free Radicals Influence

“…The uterus was chosen as an object of investigation as it is possible to obtain samples of normal and altered tissues from the same organ of the same patient so the observed changes in PALS parameters are due to the alteration only and are not related to other factors which can differ from patient to patient. Additionally, the presence of oxidative DNA damage and DNA adducts in uterus was stated before [36][37][38][39][40].…”