SCIENCE CHINA Chemistry • REVIEWS • · SPECIAL TOPIC · Research Progress of Persistent Organic Pollutants

May 2010 Vol.53 No.5: 974–979 doi: 10.1007/s11426-010-0149-1

The associations between the environmental exposure to polychlorinated biphenyls (PCBs) and breast cancer risk and progression LIU SiJin*, ZHANG ShuPing, QU Chen, LIU Wei & DU YuGuo* State Key Laboratory of Environmental Chemistry and Ecotoxicology; Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China Received January 11, 2010; accepted March 4, 2010

Polychlorinated biphenyls (PCBs) are chlorinated biphenyl compounds with wide applications in the industry. In spite of a ban on their production in the late 1970s, PCBs, as a group of POPs, are still persistent and widely spread in the environment, posing potential threats to human health. The role of PCBs as etiologic agents for breast cancer has been intensively explored in a variety of in vivo, animal and epidemiologic studies. Initial investigations indicated higher levels of PCBs in mammary tissues or sera corresponded to the occurrence of breast cancer, but later studies showed no positive association between PCB exposure and breast cancer development. More recent data suggested that the CYP1A1 m2 polymorphisms might add increased risk to the etiology of breast cancer in women with environmental exposure to PCBs. PCBs are implicated in advancing breast cancer progression, and our unpublished data reveals that PCBs activate the ROCK signaling to enhance breast cancer metastasis. Therefore, the correlation between PCB exposure and breast cancer risk warrants further careful investigations. Polychlorinated biphenyls (PCBs), environmental exposure, CYP1A1 polymorphisms, breast cancer risk, tumor progression

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Introduction

Polychlorinated biphenyls (PCBs) are a family of structurally related chlorinated aromatic hydrocarbons with 209 congeners. PCBs were once largely produced and widely used during the middle part of the last century. Although the production and massive use of PCBs were banned in the 1970s, they persist in the environment, biomagnify through food chains and accumulate in fat tissues with high residue levels in humans [1–3]. Previous studies have documented a wide spectrum of biological effects of PCBs on humans, such as immunotoxicity [4], neurotoxicity [5], and estrogenic or antiestrogenic activity [6, 7]. The association has also been implied between environmental exposure to PCBs and various types of cancers, such as prostate, testicular, *Corresponding author (email: [email protected]; [email protected]) © Science China Press and Springer-Verlag Berlin Heidelberg 2010

liver, intestine and non-Hodgkin’s lymphoma [8–10]. In the early 1990s, a few studies suggested environmental exposure to PCBs might play a significant role in the etiology of breast cancer [11, 12]. Notwithstanding, most later studies found no significant correlation between PCB exposure and the incidence of breast cancer, with possible positive correlations to some specific PCB congeners or among particular populations [9, 13, 14]. Thus whether PCBs induce procarcinogenic effects on mammary carcinoma remains inconclusive [11, 12]. Breast cancer is the most common cancer, the second most common fatal cancer in women, and the fifth most common cause of cancer death worldwide. Breast cancer incidence rates have rapidly increased in the last 5 decades, and the current estimates indicate approximately 1 out of 8 women globally will develop breast cancer over her lifetime. There is increasing evidence from epidemiological and animal studies that the initiation and progression of breast chem.scichina.com

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cancer may be considerably attributed to environmental pollution, such as the environmental endocrine-disrupting compounds [15]. The weakly estrogenic substances (e.g., PCBs and DDT) have been etiologically concerned in the development or progression of breast cancer over years. In this review, we focus on the possible procarcinogenic and prometastatic characteristics of PCBs and potential mechanisms responsible for PCB-stimulated effects on human breast cancer.

2 Environmental PCB exposure and the etiology of breast cancer The concerns with respect to likely carcinogenic influence on mammary tissues with exposure to PCBs derived from the estrogenic activity of these compounds, which have the ability to mimic or interfere with the action of endogenous hormones [15–17]. Because of their lipophilic nature, PCBs tend to accumulate in adipose tissues, and therefore could be detectable in human breast tissues and even in milk. Due to their estrogenic activity, PCBs have been documented to disrupt the endocrine systems of animals and humans [18, 19], and the combination of different PCBs could behave synergistically in presenting their estrogenic potency [20]. In addition, PCB metabolites might cause genetic damage by generating reactive intermediates within mammary cells. Back in the early 1990s, several studies were published, reporting the potential role of organochlorines in developing breast cancer. PCBs, DDT and other environmental xenoestrogens were hypothesized to be etiologic agents for human breast cancer in women based on the finding that higher burdens of plasma or mammary tissue PCBs or DDE were observed in breast cancer patients compared to control subjects [21–23]. Numerous animal studies and human epidemiological studies have been performed to determine whether environmental exposure to PCBs may contribute to increased risk of breast cancer. The results remain inconsistent, and even controversial among studies. Overall, the current data from both human and animal studies are not sufficient to support a direct association between PCB exposure and elevated breast cancer risk [9, 11, 12]. Most recent reports suggest no significant association between the serum/ plasma total PCB levels and breast cancer risk [9]. Consistent with these reports, our in vitro results suggested that the PCB mix (equal amount of No. 28, 52, 101, 138, 153, 180 and 209) had no proliferative influence on the estrogen receptor (ER)+ MCF-7 cells and ER- MDA-MB-231 cells at low concentrations, however, PCBs caused dramatic apoptosis at high concentrations (unpublished data). Although a decline has been observed for certain congeners in human subjects, the PCB levels are still of concern in the general population [24–26]. Nonetheless, positive association was found in certain population, such as Afri-

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can-American women, but not in white women [13], and postmenopausal women who had never lactated [16]. Some PCB congeners (No. 118, 156, 180 and 183) or mono-orthosubstituted PCBs (the mono-ortho congeners PCB 105, PCB 118 and PCB 156) were described to correlate to increased breast cancer risk [14, 27]. The mechanisms underlying these distinct effects from different congeners are not well known, which could be due to their diverse abilities to interfere with ER-, AhR- or other molecule/complex-induced signaling [17]. While most studies solely considered serum/ plasma PCB load, a few other studies measured PCB contents in breast fat tissues. The results from different studies seem inconsistent, similarly to those obtained from the measurements of serum PCBs. Some studies suggested positive association between tissue PCB levels and postmenopausal breast cancer [28, 29], while others showed limited or no association [30, 31]. A small number of studies suggested that PCBs might act as a risk factor for breast cancer through CYP1A1 genetic polymorphisms. Pronounced association was indicated between CYP1A1 genetic polymorphisms and increased risk of breast cancer. The relation between CYP1A1 genetic polymorphisms and breast cancer risk is discussed below. In summary, an explicit statement about the role of PCBs in the etiology of breast cancer has not been reached, despite certain biological plausibility. The correlation between PCB exposure and breast cancer risk may be due to some specific PCBs or the combination effects with other pollutants, or exist in certain subgroups of population with genetic vulnerabilities. With regard to the corresponding mechanisms, we believe that the estrogenic signaling induced by PCBs still triggers potent effects on mammary cell growth and survival.

3 Interactions between PCB exposure and CYP1A1 genetic polymorphisms CYP1A1 genetic polymorphisms have been implicated in the etiology of breast cancer in combination with PCB exposure. CYP1A1, a member of the cytochrome p450 family, is an aryl hydrocarbon hydrolase, which involves the production of reactive epoxide intermediates from polycylic aromatic hydrocarbons, steroid hormones and other aromatic compounds. The CYP1A1 activity varies among individuals, and several genetic polymorphisms of CYP1A1 (e.g., m1, m2, m3 and m4, shown in Figure 1) have been investigated for their potential association with cancer risk in that increased enzymatic activity may result in enhanced steroid metabolism, and may therefore be reasonably linked to carcinogenesis. There is no significant difference in enzymatic activity of the variant types compared to the wild type [32]. However, the CYP1A1 activity upon the CYP1A1 variants is more inducible in lymphocytes [33]. The m2 variant (an isoleucine to valine substitution occurs in the

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Figure 1 phisms.

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A schematic of the CYP1A1 reading frame. Exons 1-7 are shown with boxes. Arrows indicate the locations of m1, m2, m3 and m4 polymor-

exon 7 as shown in Figure 1, and the valine protein shows much higher enzyme activity than the isoleucine protein) correlates to greater risk of lung cancer [34] and breast cancer [34]. Concerning breast cancer, no overall association was identified between the CYP1A1 genetic polymorphisms and breast cancer risk. Considering PCB exposure, significantly increased risk of breast cancer in women with the CYP1A1 m2 variant was described in several reports. Moysich et al. first observed significantly increased risk of breast cancer in postmenopausal women with higher serum PCB levels (above the median of controls) than the control group and with at least one CYP1A1 m2 variant allele. However, in women with PCB levels lower than the median of controls, no association between the CYP1A1 m2 genotypes and breast cancer risk was observed [35]. In the following two studies, no significant independent association of either the CYP1A1 variants or total PCB levels was demonstrated to be with increased breast cancer risk. However, based on the analyses within a portion of cases from all the subjects, there was significantly increased risk of breast cancer associated with total serum PCB levels in women with the CYP1A1 m2 variant, especially in postmenopausal women [36, 37]. Another recent study further supported the association between PCB exposure and the risk of breast cancer, which was modified not only by m2 genotypes but also by m3 variants among African-American women, but not by m1 genotypes [38]. The proposed mechanism responsible for the effects mediated by CYP1A1 involves the hypothesis that polymorphic forms of CYP1A1 are more inducible by PCBs. Greater induction of CYP1A1 enzymatic activity results in enhanced metabolism of estrogen that leads to increased production of potentially toxic metabolites. Nevertheless, how could the CYP1A1 m2 polymorphic forms be induced by PCBs is not understood. It is noteworthy that no independent association between breast cancer risk and the CYP1A1 m2 variant was postulated in several other reviews [39–41]. In summary, an interactive relationship between the CYP1A1 m2 variants and PCB load could exist in vivo, which contributes to increased breast cancer risk, predominantly in postmenopausal women. The authors conceive that the enhanced estrogen metabolism induced by PCBs upon

the genetic CYP1A1 variations is crucial in facilitating carcinogenesis.

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PCB exposure and breast cancer prognosis

The real threat to lives of breast cancer patients is not the primary tumor, but metastasis to distant organs which accounts for poor prognosis and 90% of deaths of breast cancer patients. Once breast cancer cells form secondary tumors, the disease essentially enters an incurable phase. Several lines of evidence suggested that some particular PCB congeners were correlated with more aggressive mammary tumors [42–44]. An epidemiological study suggested that high concentrations of PCBs in mammary adipose tissues were associated with high-grade tumors and overall poor prognosis in breast cancer patients [44]. The mechanisms underlying PCB-promoted mammary tumor progression and deterioration remain unexplored. We demonstrated that PCBs tremendously facilitate the in vitro motility and the in vivo metastatic properties of breast cancer cells by increasing the Rho-associated kinase (ROCK) activity via induction of intracellular reactive oxygen species (ROS) (unpublished data). Members of Rho small GTPases play a crucial role in regulating cell morphology, growth, apoptosis and motility. ROCK (two isoforms, ROCK 1 and 2) is the major downstream mediator of the Rho activity [45]. ROCK is implicated in the regulation of in vitro invasion and motility and in vivo metastasis of breast cancer and other cancers [46]. ROCK overexpression enhances invasion and migration of tumor cells [47–49]. Conversely, inhibition on the ROCK activity by introduction of a dominant-negative ROCK or addition of the ROCK inhibitor (Y27632) has been found to suppress cancer cell invasion and migration in vitro and motility and dissemination in animal models [48, 50]. Our recent report showed that the expression of ROCK was robustly increased in human breast cancer tumors with metastases than those without metastases [51]. Overexpression of ROCK endowed nonmetastatic MCF-7 breast cancer cells with metastatic properties [51]. On the contrary, the expression of the ROCK-shRNAs and the selective ROCK inhibitor, Y27632, significantly suppressed metastasis of

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SUM1315 breast cancer cells [51]. Thus activation of ROCK by PCBs may present a novel mechanism in interpreting the correlation between PCB accumulation in mammary fat and poor prognosis in breast cancer patients as discussed previously [44], although the molecular bases implicated in this mechanism remain to be further elucidated.

5

Conclusions and perspectives

PCBs are widespread and persistent environmental pollutants that impose potential hazards on human health. Earlier studies proposed that the high body burden of PCBs could be a significant factor for the etiology in the development of breast cancer. This proposal is not confirmed by the more recent in vitro, animal and epidemiological studies. However, the possible correlation between environmental PCB exposure and breast cancer risk cannot be conclusively excluded based on the current literature. Most studies relied on serum/plasma PCB measurements, rather than direct mammary adipose tissue measurements. The levels when tested may not represent the levels present when the disease is initiated. For example, PCBs could be mobilized upon chemotherapy treatments [52]. Thus the serum/plasma PCB levels may not be able to reflect the most relevant levels in breast, and they may fail to be an indicator in disclosing the

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possibility of PCB-induced effects. Mounting evidence indicates that PCB exposure contributes to the aggressiveness and metastases of breast cancer, and our own data suggests PCBs could potently increase breast cell motility and advance breast cancer progression, although the mechanisms related to these findings are not fully recognized. Although the incidence of breast cancer has significantly increased over the past 50 years all over the world, the cause of this rise is not fully understood. The risk factors from environmental pollution have been extensively investigated for a number of years, however, the contribution of PCBs or other organochlorine compounds to breast cancer development and progression is not conclusive at this point. Studies suggest that PCBs evoke significant effects on cell growth, survival and motility of mammary cells by interrupting the endogenous estrogen signaling and yielding intracellular ROS, as illustrated in Figure 2. The CYP1A1 polymorphisms could modify PCB-mediated tumorigenic effects by changing the CYP1A1 enzymatic activity (Figure 2). Future investigations may involve the role of PCBs in regulating breast cancer progression and metastasis rather than the disease development alone, the vulnerable population (such as individuals with higher levels of PCBs in sera and fat tissues), the more etiologically relevant periods (such as in postmenopausal women), the combined effects along with exposure to other pollutants, and gene-environment interactions (e.g., genetic polymorphisms).

Figure 2 A schematic of the PCB-induced signaling in breast cancer cells. PCB exposure exerts biologically meaningful influences on cell growth, motility and death via at least two pathways: 1) by interfering with the endogenous ER-mediated signaling; and 2) by producing ROS. The CYP1A1 polymorphisms may exacerbate PCB-promoted tumorigenesis by increasing estrogen metabolism.

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The authors express their great thanks for the support from the Hundred Talents Program of the Chinese Academy of Sciences and the National Natural Science Foundation of China (20921063).

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