Hormones and Hormone Antagonists: Mechanisms of Action in Carcinogenesis of Endometrial and Breast Cancer

Flötotto, T; Djahansouzi, S.; Gläser, Michael; Hanstein, Bettina; Niederacher, Dieter; Brumm, C.; Beckmann, Matthias W.

doi:10.1055/s-2001-16936

Cited by 65 publications

(39 citation statements)

References 53 publications

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“…In support of our findings, previous studies (27-29) have shown beneficial effects of HRT use for lung cancer risk. For example, Kreuzer et al The potential of estrogens to initiate and promote tumor growth in female reproductive organs by interacting with estrogen receptors, which are also present in both normal (40) and malignant lung tissue (40 -42), is well established (41,43,44). However, their role in lung cancer tumorigenesis is unclear.…”

Section: Discussionmentioning

confidence: 99%

Hormone Replacement Therapy and Lung Cancer Risk

Schabath¹,

Wu²,

Vassilopoulou‐Sellin

et al. 2004

Clinical Cancer Research

165

129

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Purpose: To date, there are few published data regarding the use of hormone replacement therapy (HRT) and lung cancer risk. Therefore, we analyzed data regarding HRT use from a large case-control study designed to study genetic susceptibility to lung cancer to determine whether HRT affected risk of lung cancer.Experimental Design: In a secondary analysis, we compared self-reported HRT use among 499 women with lung cancer and 519 healthy age-matched controls.Results: HRT use was associated with an overall reduced risk of 34% [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.51-0.89] of lung cancer, after adjusting for age, ethnicity, smoking status, education, body mass index, and menopausal status. The use of estrogen replacement therapy alone was associated with a 35% reduction in lung cancer risk (OR, 0.65; 95% CI, 0.47-0.89) and the use of combination therapy (estrogen and progestin) was associated with a 39% reduction in lung cancer risk (OR, 0.61; 95% CI, 0.40 -0.92). HRT use was also associated with a statistically significantly reduced risk of lung cancer in current smokers (OR, 0.59; 95% CI, 0.38 -0.92), but the risk estimates were not statistically significant in never (OR, 0.72; 95% CI, 0.37-1.40) or former smokers (OR, 0.73; 95% CI, 0.46 -1.15). In addition, as the cigarette pack-years increased among ever smokers, the protective effect diminished, so that light smokers appeared to benefit the most from HRT use. Decreased lung cancer risks were also evident when the data were stratified by age, ethnicity, and body mass index. The joint effects of HRT use and mutagen sensitivity suggest that HRT use modifies lung cancer risk for genetically susceptible women. HRT use was also associated with a lower risk of death and improved survival compared with the women not taking HRT. To provide a possible biological mechanism to explain our findings, we compared plasma levels of insulin-like growth factor I in users and nonusers, and demonstrated that HRT use was associated with statistically significantly lower insulin-like growth factor I levels for both cases and controls compared with non-HRT users.Conclusions: These data suggest an association of HRT use with a decrease in lung cancer risk. However, there are several limitations to this secondary analysis, requiring that the data be viewed with caution, and confirmation is required in well-designed hypothesis driven studies. The biological role of HRT in lung cancer remains understudied, and only extensive research can yield new insights into the mechanisms underlying a protective effect of HRT for lung cancer.

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Section: Discussionmentioning

confidence: 99%

Hormone Replacement Therapy and Lung Cancer Risk

Schabath¹,

Wu²,

Vassilopoulou‐Sellin

et al. 2004

Clinical Cancer Research

165

129

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“…The collective evidence supports contributions to estrogensensitive breast cancer from both the proliferative and antiapoptotic hormonal effects of estrogen itself (12)(13)(14)(15)(16) and the genotoxic and mutagenic effects of estrogen metabolites (17,18). In human breast tissue, estrogen metabolites have been detected (19), and DNA adducts of equine estrogens have been reported (20).…”

mentioning

confidence: 94%

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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“…Regulation of proliferation and differentiation and essential pathways involved in the physiological action of estrogen and progesterone in target tissues are well documented (Graham and Clarke, 1997;Sutherland et al, 1998). Furthermore, several in vivo and in vitro reports clearly indicate that these hormones are also implicated in the control of cell loss by apoptosis (Kumar et al, 2000), but these data remain controversial because, depending on the experimental model, both anti-and pro-apoptotic activity has been ascribed to each hormone (Flototto et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Progesterone prevents radiation-induced apoptosis in breast cancer cells

Varès¹,

Ory²,

Lectard³

et al. 2004

Oncogene

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Sex steroid hormones play an essential role in the control of homeostasis in the mammary gland. Although the involvement of progesterone in cellular proliferation and differentiation is well established, its exact role in the control of cell death still remains unclear. As dysregulation of the apoptotic process plays an important role in the pathogenesis of breast cancer, we investigated the regulation of apoptosis by progesterone in various breast cancer cell lines. Our results show that progesterone treatment protects against radiation-induced apoptosis. This prevention appears to be mediated by the progesterone receptor and is unrelated to p53 status. There is also no correlation with the intrinsic hormonal effect on cell proliferation, as the presence of cells in a particular phase of the cell cycle. Surprisingly, progesterone partly allows bypassing of the irradiation-induced growth arrest in G 2 /M in PgR þ cells, leading to an increase in cell proliferation after irradiation. One consequence of this effect is a higher rate of chromosome damage in these proliferating progesterone-treated cells compared to what is observed in untreated irradiated cells. We propose that progesterone, by inhibiting apoptosis and promoting the proliferation of cells with DNA damage, potentially facilitates the emergence of genetic mutations that may play a role in malignant transformation.

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Hormones and Hormone Antagonists: Mechanisms of Action in Carcinogenesis of Endometrial and Breast Cancer

Cited by 65 publications

References 53 publications

Hormone Replacement Therapy and Lung Cancer Risk

Hormone Replacement Therapy and Lung Cancer Risk

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

Progesterone prevents radiation-induced apoptosis in breast cancer cells

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