Cancer Letters

Cancer Letters

Volume 308, Issue 1, 1 September 2011, Pages 14-22
Cancer Letters

Estrogen promotes benzo[a]pyrene-induced lung carcinogenesis through oxidative stress damage and cytochrome c-mediated caspase-3 activation pathways in female mice

https://doi.org/10.1016/j.canlet.2011.04.007Get rights and content

Abstract

Estrogen may contribute to the development of smoking-induced lung cancer in women. To test this hypothesis, an mouse model was used to investigate the effects of 17 beta-estradiol (E2) on benzo[a]pyrene (B[a]P)-induced lung carcinogenesis. We found that B[a]P could cause oxidative stress damage, upregulate mitochondrial cytochrome-c and caspase-3 expression, induce lung carcinogenesis in female mice, E2 promoted these effects of B[a]P while tamoxifen (TAM) inhibited this effects of E2. We conclude that E2 can promote the tumorigenic effects of B[a]P in female mice, and oxidative stress damage and activation of cytochrome-c-mediated caspase-3 pathway may be involved in this process.

Highlights

► Estrogen may contribute to the development of smoking-induced lung cancer in women. ► We examine the effects of estradiol on benzo[a]pyrene-induced lung carcinogenesis. ► B[a]P cause oxidative stress, upregulate Cyt-c and caspase-3, induce lung cancer. ► E2 promote these tumorigenic effects of B[a]P in female mice. ► Activation of Cyt-c-mediated caspase-3 pathway may be involved in this process.

Introduction

Lung cancer is the leading cause of cancer death worldwide, especially in the United States [1], [2], Europe [3], and China [4]. Presently, lung cancer accounts for more deaths in women than any other cancer, and this number is more than the combined number of the second and third most fatal cancers in women (breast and colon cancer, respectively [5]. It is a well-established fact that cigarette smoking is the principal cause of lung cancer in both men and women. The majority of studies in the past have reported that the risk of lung cancer is higher in male smokers than that in female smokers [6], [7]. However, several recent studies have indicated that the absolute risk for lung cancer is higher for women than for men [8], [9], [10], [11]. Recently, the International Early Lung Cancer Action Program Investigators reported that women who smoke are at a high risk of lung cancer than men of the same age who smoke the same number of cigarettes [5]. This is the first prospective cohort study in which such a gender difference has been observed. In our recent experiments, we found a similar result that gender differences may influence the occurrence of smoke-induced lung tumors and antioxidant intervention in mice [12]. We hypothesized that hormonal factors could provide a possible explanation for these gender-based differences in lung cancer. Some data confirmed this hypothesis from the results of epidemiological investigations [10], [11], [13], [14], [15], [16] and cell lines experiments [17]. However, to date, there is no in vivo direct evidence to support this hypothesis.

Benzo[a]pyrene (B[a]P) is one of the main carcinogens in cigarette smoke, and also a known human carcinogen [18]. Because of the carcinogenic effects of B[a]P, it has been utilized as a tool reagent to induce lung tumorigenesis in the evaluation of in vivo carcinogenic assay systems [19], [20], [21]. Estrogen is one of the vital hormones that regulate lung development [22]. Several reports of sex differences in lung cancer risk and disease presentation suggest that use of hormone-replacement therapy (HRT) was associated with a higher risk of adenocarcinoma of the lung compared with never use, and a positive interaction was noted between HRT, smoking, and adenocarcinoma of the lung [23], and estrogen may be involved in the etiology of lung cancer, particularly adenocarcinoma in women [24]. Additionally, 17-beta-estradiol acts as a mitogen for NSCLC cells in vitro and in vivo [13] and can modulate the expression of genes in NSCLC cell lines that are important for control of cell proliferation [25]. The drug tamoxifen (TAM) is the most widely used drug for the treatment of estrogen receptor (ER)-positive breast cancer, and exerts its antiestrogenic effect both by displacing the growth-promoting natural hormone estradiol-17beta from its receptor [26] and by blocking the stimulatory effects of IL-6 on 17beta-OH steroid dehydrogenase [27]. TAM works by competitively blocking the binding of estrogens to the ER, which leads to inhibition of estrogen-responsive genes such as those responsible for growth and angiogenesis within the tumor [28].

In the present study, we comprehensively evaluated the role of 17 beta-estradiol (E2) in promoting the genesis of lung cancer induced by benzo[a]pyrene (B[a]P) in female mice, and investigated the effects of E2 on B[a]P induced oxidative stress damage and cytochrome c-mediated activation of caspase-3 pathways.

Section snippets

Chemicals

Estrogen [17 beta-estradiol (E2)], B[a]P, tamoxifen (TAM), and olive oil were all purchased from Sigma–Aldrich company (USA).

Animals

Healthy 5-week-old female Swiss mice (Kunming mice; weight, 18 ± 2 g) were purchased from Center of Animal, Academy of Military Medical Sciences, Beijing, China. The mice did not show any signs of infectious disease (pathogenic agents). They were housed in polypropylene cages with tight-fitting wire screen lids made of conventional bedding materials. The mice were monitored

Changes of mice body weights and survival rate curves of the mice during the experiment

All animals showed good tolerance to E2, TAM, and B[a]P exposure. There was no death due to experimental factors throughout the study. Overall, body weight was the lowest in the B[a]P + TAM + E2 group, and this weight was significantly lower than that in the control group (P < 0.05). The body weights of mice in other groups did not differ significantly, but the body weight of the B[a]P-exposed mice was lower than that of the mice in other groups (P > 0.05) (Supplementary materials, S-Figure 1). Only a

Discussion

In this study, we developed an animal model to evaluate the role of E2 in the development and growth of lung cancer induced by B[a]P, which was one of the main carcinogens in cigarette smoke [32], [33]. In the present study, we found that E2, by itself, did not induce lung tumor. However, E2 promoted B[a]P that in turn induced lung cancer in female mice; TAM inhibited the effects of E2 that promoted B[a]P-induced carcinogenesis. These findings indicated that estrogen might be a carcinoma

Financial disclosure

This research received no external funding.

Conflict of interest

The authors have declared that no competing interests exist.

Acknowledgments

We thank Jian Tao and Yufei Zheng for their assistance in performing some experiments. We also thank Zhuge Xi, Qiang Ma, Jinpeng Guo, Zuguo Zhao, Xiaoying Zhang, Danfeng Yang, Jing Yin for reagents and experimental assistance.

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