Clinical Science Review: Estrogen Use and Cancer Incidence: A Review

Lupulescu, A.

doi:10.3109/07357909509094464

Cited by 49 publications

(36 citation statements)

References 33 publications

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“…Tumour formation may result from excessive hormonal stimulation of an organ in which normal growth and function is under endocrine control [28]. Although the exact molecular mechanisms during the process of breast cancer development are not fully elucidated, promotion of proliferation in the breast tissue is believed to be a key event [29]. There is concern that, in addition to endogenous hormones, xenoestrogens and inappropriate exposure to phytoestrogens may promote this process too [3], [11].…”

Section: Discussionmentioning

confidence: 99%

Effects of Genistein on the Mammary Gland Proliferation of Adult Ovariectomised Wistar Rats

et al. 2006

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The effects of phytoestrogens on the female breast are discussed controversially. On the one hand, epidemiological and experimental data provide evidence that dietary phytoestrogens may prevent the development of breast cancer. On the other hand, in breast cancer cell lines and tumour models isoflavone phytoestrogens have been demonstrated to stimulate the growth of estrogen-dependent breast cancer cells. To further investigate the molecular effects of genistein (Gen) on the mammary gland, we treated non-tumour bearing, ovariectomised female Wistar rats with this phytoestrogen either subcutaneously (10 mg/kg body weight) or orally (100 and 200 mg/kg body weight) for 3 days. Estradiol (E(2), 0.004 mg/kg s. c.) and ethynylestradiol (EE, 0.1 mg/kg per os) served as reference compounds. In the breast tissue, mRNA and protein expression of the progesterone receptor (marker for estrogenicity) and PCNA (marker gene for proliferation) were examined by quantitative real-time PCR, Western blotting and immunohistochemistry; the uterotrophic response was assessed also. Treatment with Gen per os or s. c. results in a small but significant stimulation of the uterine wet weight. In the mammary gland, Gen stimulates the expression of progesterone receptor (PR) but, in contrast to E(2), the isoflavone does not stimulate the expression of PCNA. These findings resemble recent data demonstrating a differential ability of Gen to induce uterine gene expression and uterine proliferation. Our data indicate that in non-malignant breast tissue short-term administration of Gen, in contrast to more potent estrogens like E(2), does not induce proliferation. Chronic stimulation of proliferation is believed to be a key mechanism during the development of breast cancer. The limited ability of Gen to stimulate proliferation in this tissue could be an indication for a limited carcinogenic potency of Gen in the breast. In further investigations it is important to identify molecular differences between healthy and malignant breast tissue which may explain the different sensitivity towards Gen treatment.

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Section: Discussionmentioning

confidence: 99%

Effects of Genistein on the Mammary Gland Proliferation of Adult Ovariectomised Wistar Rats

et al. 2006

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“…Observations from various clinical trials and epidemiological studies collectively support the hypothesis that estrogen contributes to breast cancer and is probably causative (2)(3)(4)(5)(6)(7)(8). The large prospective Women's Health Initiative Study comparing postmenopausal women assigned HRT/ERT or placebo was terminated because of significant increases in breast cancer, stroke, and pulmonary embolism associated with therapy (9,10).…”

mentioning

confidence: 83%

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

Wang

Wijewickrama

Peng

et al. 2009

Journal of Biological Chemistry

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Exposure to estrogens increases the risk of breast and endometrial cancer. It is proposed that the estrogen receptor (ER) may contribute to estrogen carcinogenesis by transduction of the hormonal signal and as a "Trojan horse" concentrating genotoxic estrogen metabolites in the nucleus to complex with DNA, enhancing DNA damage. 4-Hydroxyequilenin (4-OHEN), the major catechol metabolite of equine estrogens present in estrogen replacement formulations, autoxidizes to a redox-cycling quinone that has been shown to cause DNA damage. 4-OHEN was found to be an estrogen of nanomolar potency in cell culture using a luciferase reporter assay and, using a chromatin immunoprecipitation assay, was found to activate ER␣ binding to estrogen-responsive genes in MCF-7 cells. DNA damage was measured in cells by comparing ER␣(؉) versus ER␣(؊) cells and 4-OHEN versus menadione, a reactive oxygen species (ROS)-generating, but non-estrogenic, quinone. 4-OHEN selectively induced DNA damage in ER␣(؉) cells, whereas menadione-induced damage was not dependent on cellular ER status. The rate of 4-OHEN-induced DNA damage was significantly enhanced in ER␣(؉) cells, whereas ER status had no effect on the rate of menadione-induced damage. Imaging of ROS induced by 4-OHEN showed accumulation selective for the nucleus of ER␣(؉) cells within 5 min, whereas in ER␣(؊) or menadione-treated cells, no selectivity was observed. These data support ER␣ acting as a Trojan horse concentrating 4-OHEN in the nucleus to accelerate the rate of ROS generation and thereby amplify DNA damage. The Trojan horse mechanism may be of general importance beyond estrogen genotoxins.An increased relative risk of breast cancer in postmenopausal women is strongly linked to several endocrine-related risk factors. One of these risk factors is long-term exposure to hormone or estrogen replacement therapy (HRT 3 or ERT). The most widely prescribed formulations in the United States contain conjugated human estrogens and B-ring unsaturated conjugated equine estrogens, the latter constituting approximately half of the estrogen content of these formulations (1). Observations from various clinical trials and epidemiological studies collectively support the hypothesis that estrogen contributes to breast cancer and is probably causative (2-8). The large prospective Women's Health Initiative Study comparing postmenopausal women assigned HRT/ERT or placebo was terminated because of significant increases in breast cancer, stroke, and pulmonary embolism associated with therapy (9, 10). A recent analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries showed that the age-adjusted incidence rate of breast cancer fell 6.7% in 2003 compared with 2002, which was linked to lowered use of HRT/ERT (11). The collective evidence supports contributions to estrogensensitive breast cancer from both the proliferative and antiapoptotic hormonal effects of estrogen itself (12-16) and the genotoxic and mutagenic effects of estrogen metabolites (...

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“…Hormonal risk is one of the non-genetic factors that may contribute to the disease's etiology. Several clinical, epidemiological and experimental studies have proved that estrogen and progesterone play a major role in the growth of normal breast tissue (Lupulescu 1995;Berstein and Press 1998), and breast cancer risk is strongly related to exposure to these endogenous steroid hormone levels (Pike et al 2004), specifically estrogen (Feigelson and Henderson 1996). Although the exact mechanisms remain to be fully elucidated, the alkylation of cellular molecules and the generation of active radicals that can damage DNA (Nandi et al 1995), together with the potential genotoxicity of estrogen and some of its metabolites (e.g.…”

Section: Introductionmentioning

confidence: 99%

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

Chakraborty

Murthy²,

Chintamani

et al. 2007

J Hum Genet

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A single T > C change at the 5¢ promoter region of the CYP17 gene is reported to be associated with increased risk of breast cancer. This study evaluates the influence of genetic polymorphism of CYP17 on breast cancer susceptibility. Two hundred and fortytwo patients with histopathologically confirmed breast cancer and 212 age-matched controls were included in the present study. Information relating to age at onset of the disease, family history and estrogen receptor status was elicited. Investigation for CYP17 polymorphism was carried out in 106 early onset, 80 late onset and 56 familial cases. The frequencies of two CYP17 alleles were also analyzed in 116 (47.9%) cases with known estrogen receptor (ER) status confirmed immunohistochemically. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the polymorphism, and the genotypes identified were assigned as homozygous wild type (A1A1), heterozygous variant (A1A2), and homozygous variant (A2A2). Associations between the various genotypes in patients and controls were investigated with Fisher's exact test. All the tests were two tailed. The results showed that the frequency of heterozygous and homozygous CYP17 genotype was higher in early onset breast cancer patients (94.3%) than in controls (80.3%), and the difference was significant (P = 0.001). A highly statistically significant increased risk in carriers of homozygous A2 allele was found in young patients (P £ 0.001) in comparison with patients having late onset condition (P = 0.260). However, no significant association between the genotype and breast cancer risk was observed among women with strong family history. Further, data had showed that patients (80.6%) with at least one A2 allele tended to exhibit ER-independent cell proliferation, although statistical significance could not be established (P = 0.160). The present findings suggest that CYP17 A2 allele gene polymorphism might play a significant role in breast cancer development in young Indian women.

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Clinical Science Review: Estrogen Use and Cancer Incidence: A Review

Cited by 49 publications

References 33 publications

Effects of Genistein on the Mammary Gland Proliferation of Adult Ovariectomised Wistar Rats

Effects of Genistein on the Mammary Gland Proliferation of Adult Ovariectomised Wistar Rats

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

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