Prevention of tobacco carcinogen-induced lung cancer in female mice using antiestrogens

Stabile, Laura P.; Rothstein, Mary E.; Cunningham, D.; Land, Stephanie R.; Đačić, Sanja; Keohavong, Phouthone; Siegfried, Jill M.

doi:10.1093/carcin/bgs260

Cited by 47 publications

(72 citation statements)

References 43 publications

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“…In human breast cancer, patients treated with anastrozole showed a reduction in Ki67 index, two months after the treatment onset [20]. In mouse lung cancer induced by tobacco carcinogen NNK, anastrozole also produce a decrease in the Ki67 cell proliferation index demonstrating the effectiveness of this medication in several cancer types [21]. Thus, our results encourage us to test this medication for GBM treatment in the human being.…”

Section: Discussionsupporting

confidence: 54%

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

García¹,

Ramirez²,

Jiménez³

et al. 2017

J Cancer Sci Ther

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Objective: Glioblastoma multiforme is the most aggressive form of primary brain tumors, characterized by a high molecular heterogeneity hinder its treatment. Glioblastoma multiforme cells synthesize steroids through the enzyme aromatase and express estrogen receptors. Anastrozole, a specific aromatase inhibitor, plays an important role in endocrine therapy for breast cancer treatment. However, it is unknown whether this inhibitor is useful for treating glioblastoma multiforme. The aim of this work was evaluated the anastrozole effects in the viability and proliferation of malignant cells C6 in vitro as well as apoptosis, cell division, aromatase and estrogen receptor alpha expression in a GBM model in vivo.Methods: C6 cells viability under anastrozole treatment (25, 50, 75 µg/ml) was measured by MTT method and their proliferation was determinate by immunohitofluorescence. In the tumor tissue, the proliferation was evaluated using ki-67 antibody by immunohistofluorescence. ER alpha, aromatase, caspase 8 and 9 protein expression was analyzed using western-blotting. Furthermore, GPR-30, SOX2, CD133 and GFAP were evaluated by immunohistofluorescence.Results: Anastrozole produced a reduction in the viability and proliferation of the C6 cells in culture when was used at 50 μg/ml. It reduces the number of Ki67 immunofluorescent cells in approximately 50%. The aromatase expression decreased in 95%. The estrogen receptor alpha expression increased by a 20% approximately. Caspase 8 expression increased in the treated tumor tissue, although it was undetectable in the not treated group. Caspase 9 increased in approximately 95% in the treated group. All data expressed in these experimental quantifications have a statistically significant difference (p<0.05). G protein coupled receptor-30 was observed in the tumor specimens exhibiting an expression reduction in the anastrozole treated group. Conclusion:The present study demonstrates that anastrozole reduces viability and proliferation in vitro, induces apoptosis and reduces proliferation and aromatase expression in the glioblastoma Xenograft mouse model.

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Section: Discussionsupporting

confidence: 54%

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

García¹,

Ramirez²,

Jiménez³

et al. 2017

J Cancer Sci Ther

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“…We showed that tissue aromatase is expressed in the lungs, especially in pulmonary macrophages [16]. The AI anastrozole and/or the anti-estrogen fulvestrant were administered as described and the published data showed that these agents, especially in combination, effectively inhibited NNK-induced lung adenoma formation by up to 75%, and also reduced the number of preneoplasias [16].…”

Section: Resultsmentioning

confidence: 99%

Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer

et al. 2017

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The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog. Mice administered β-estradiol during carcinogen exposure showed increased FGF2, FGF9, SOX2, and Nanog expression in airway preneoplasias. In normal FGFR1 copy number NSCLC cell lines, multiple FGFR receptors were expressed and secreted several FGFs. β-estradiol caused enhanced FGF2 release, which was blocked by fulvestrant. Upon co-inhibition of ER and FGFRs using fulvestrant and the pan-FGFR inhibitor AZD4547, phosphorylation of FRS2, the FGFR docking protein, was maximally reduced, and enhanced anti-proliferative effects were observed. Combined AZD4547 and fulvestrant enhanced lung tumor xenograft growth inhibition and decreased Ki67 and stem cell marker expression. To verify a link between ERβ, the predominant ER in NSCLC, and FGFR signaling in patient tumors, mRNA analysis was performed comparing high versus low ERβ expressing tumors. The top differentially expressed genes in high ERβ tumors involved FGF signaling and human embryonic stem cell pluripotency. These results suggest interaction between the ER and FGFR pathways in NSCLC promotes a stem-like state. Combined FGFR and ER inhibition may increase the efficacy of FGFR inhibitors for NSCLC patients lacking FGFR genetic alterations.

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“…Moreover, CS was found to accelerate the production of the carcinogenic estrogenic metabolites 4-OHEs in the lungs (76), and the role that estrogen-metabolizing enzymes such as Cytochrome P450 1b1 (CYP1B1) may have in the enhanced female genderrelated susceptibility to tobacco has also been previously reported (75,81,82). The CS carcinogen nicotine-derived nitrosamine ketone (NNK) was shown to induce ERα via CYP1B1 activation (83), and anti-estrogens effectively inhibited NNK-induced murine lung carcinogenesis (84).…”

Section: Sex Differences In Lc Susceptibilitymentioning

confidence: 89%

A potential role for estrogen in cigarette smoke-induced microRNA alterations and lung cancer

Cohen

Burgos-Aceves²,

Smith³

2016

Transl. Lung Cancer Res.

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Alteration in the expression of microRNAs (miRNAs) is associated with oncogenesis and cancer progression. In this review we aim to suggest that elevated levels of estrogens and their metabolites inside the lungs as a result of cigarette smoke exposure can cause widespread repression of miRNA and contribute to lung tumor development. Anti-estrogenic compounds, such as the components of cruciferous vegetables, can attenuate this effect and potentially reduce the risk of lung cancer (LC) among smokers. (Table 1), and seem to work differently depending on the cellular context (47). However, developing any type of LC by deregulation of miRNAs via ER-Estrogen effect is still not entirely clear (8). miRNAs repression by cigarette smoke in the lungsWe have summarized before the results showing reduced expression levels of miRNAs in various tumors and cancer cell lines, including LC (48). The observation of a global miRNA repression in the lungs of rodents exposed to CS has also been reported (49)(50)(51)(52). Izzotti et al. show in their results the extensive down-regulation of 126 miRNAs in lungs of rats, 4 weeks after CS exposure (49). Such a short-lasting exposure to CS resulted in reversible miRNA alterations, as miRNA down-regulation was considerably attenuated one week after smoking cessation (51). By contrast, the repression of miRNA detected in mice exposed to CS for 4 months still persisted 3 months after smoking cessation, with the progressive development of cancer in the lung, suggesting that long-lasting exposure is needed to induce irreversible miRNA alterations (51,53). In their previous published results, using the same animal model, Izzotti et al. have found that CS up-regulates gene transcription and protein expression (54,55). The authors suggested that the CS-induced down-regulation of miRNA cause oncogene activation and cell proliferation, and that the persistence of these molecular alterations is crucial to commit lung cells towards carcinogenesis (51,53). These results are supported by the study of Schembri et al., who found that most of the differentially expressed miRNAs in the human bronchial airway epithelium were downregulated in smokers and were inversely correlated with their predicted targets (56). The same phenomenon was also observed in alveolar macrophages of smokers, where CS decreased global miRNA expression, while increased their predicted targets (57). In this later study the decrease in global miRNA expression was more pronounced in heavy smokers, suggesting that the magnitude of miRNA repression is related to the extent of smoking history (57). Anti-estrogenic compounds as attenuators of cigarette smoke effectsStudies suggest that phytochemicals from vegetables and fruits exhibit chemopreventive activities against various types of cancer (58). Izzotti et al. (59) evaluated miRNA expression in the lungs of rats exposed to CS and treated with several cancer chemopreventive agents. Administration of the dietary agents, Phenethyl isothiocyanate (PEITC) and Indole-3-carbi...

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Prevention of tobacco carcinogen-induced lung cancer in female mice using antiestrogens

Cited by 47 publications

References 43 publications

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer

A potential role for estrogen in cigarette smoke-induced microRNA alterations and lung cancer

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