Associations of persistent organic pollutants in serum and adipose tissue with breast cancer prognostic markers

https://doi.org/10.1016/j.scitotenv.2016.04.188Get rights and content

Highlights

  • The role of POP exposure on the pathogenesis breast cancer is still controversial.

  • POPs were analyzed in serum and adipose tissue from breast cancer patients.

  • POP concentrations were associated with breast cancer prognostic markers.

  • POPs in serum and adipose tissue of breast cancer patients may provide different clues.

Abstract

This study aimed to evaluate associations between exposure to a group of persistent organic pollutants, measured in both adipose tissue and serum samples from breast cancer patients, and a set of tumor prognostic markers. The study population comprised 103 breast cancer patients recruited in Granada, Southern Spain. Data for tumor prognostic markers were retrieved from hospital clinical records and socio-demographic information was gathered by questionnaire. Persistent organic pollutants were quantified by gas chromatography with electron capture detection. Exposure levels were categorized in quartiles, and associations were evaluated using unconditional logistic regression. Adipose tissue HCB concentrations were associated positively with ER and PR expression (p-trends = 0.044 and 0.005, respectively) and negatively with E-Cadherin and p53 expression (p-trends = 0.012 and 0.027, respectively). PCB-180 adipose tissue concentrations were positively associated with HER2 expression (p-trend = 0.036). Serum PCB-138 concentrations were positively associated with ER and PR expression (p-trends = 0.052 and 0.042, respectively). The risk of p53 expression was higher among women in the lowest quartile of serum PCB-138 concentrations, but no significant trend was observed (p-trend = 0.161). These findings indicate that human exposure to certain persistent organic pollutants might be related to breast cancer aggressiveness. We also highlight the influence on exposure assessment of the biological matrix selected, given that both serum and adipose tissue might yield relevant information on breast cancer prognosis.

Introduction

Breast cancer represents around 25% of all cancers and is the most frequent cancer in women (Ferlay et al., 2015). Its incidence continues to rise in most countries (Parkin et al., 2005, World Cancer Research Fund International, 2014), and this increase cannot solely be explained by the introduction of mammography screening (Soto and Sonnenschein, 2015). Epidemiological studies have identified risk factors for the disease, including age, family history, and genetics, but these only account for a relatively small proportion of cases (Ellsworth et al., 2015, Knower et al., 2014). Further research is required on the mechanisms underlying the development of breast cancer and on the risk factors for this disease (Reaves et al., 2015).

There is growing evidence of the potential role in the pathogenesis of breast cancer of long-term exposure to low doses of certain environmental pollutants. Persistent organic pollutants (POPs) constitute a group of particular interest because of their ubiquitous presence in the environment and the virtually universal and often daily exposure of humans to these substances (UNEP, 2003). POPs include organochlorine pesticides, which have long been widely used in agriculture and public health as pest control agents (UNEP, 2003), and polychlorinated biphenyls (PCBs), which are employed worldwide in numerous industrial and commercial applications (La Rocca and Mantovani, 2006). POP production and use has been banned in most countries, but their lipophilicity and resistance to degradation favors their bioaccumulation, and they are found in virtually all human populations and biological matrices, with diet (especially fatty food) being the main route for human exposure (Arrebola et al., 2009, Brauner et al., 2012).

It is well known that breast cancer can be promoted by dysregulation of the estrogen balance (Subramanian et al., 2008). In fact, many of the best-documented risk factors for breast cancer are related to hormonal homeostasis or estrogenic impregnation, including age, hormonal status, age at puberty, menopausal status, age at first child, breast feeding, use of oral contraception, or receipt of postmenopausal hormone replacement therapy (McPherson et al., 2000).

Some organochlorine pesticides and PCBs were initially suspected of being carcinogens due to their estrogenic properties (Kupfer and Bulger, 1977). In fact, experimental findings have indicated that exposure to certain POPs can have estrogen-related effects, including an increase in uterine weight (Adami et al., 1995) or the promotion of estrogen-related tumors (Scribner and Mottet, 1981). In this regard, numerous POPs have been shown to interact with estrogen and/or androgen receptors and with their binding hormones (Andersen et al., 2002, Arrebola et al., 2012, Aube et al., 2011, Bonefeld-Jorgensen et al., 2001, Grunfeld and Bonefeld-Jorgensen, 2004, Lemaire et al., 2006, Soto et al., 1994). However, carcinogenesis is a complex and lengthy process involving initiation, promotion, and progression, and any of these steps can potentially be disrupted (Belpomme et al., 2007). It has also been reported that POPs may not necessarily cause cancer themselves but may act as co-carcinogens (Landau-Ossondo et al., 2009). Thus, Johnson et al. (2012) found that p,p′-DDE promoted but did not induce carcinogenesis in experimental models, while various authors reported that some OCPs significantly reduce the survival of breast cancer patients (Hoyer et al., 2000, Parada et al., 2015) and that chronic exposure can negatively affect the growth inhibition system that commonly downregulates the cell cycle in abnormal conditions (Nahta et al., 2015). It has also been suggested that POPs might be associated with cancer development by mechanisms unrelated to estrogen receptors, such as the induction of oxidative stress (Arrebola et al., 2014). Furthermore, some researchers have suggested that POP exposure may be related not only to the onset of breast cancer but also to a worse prognosis (Cohn et al., 2007, Hoyer et al., 2000, Hoyer et al., 2001).

The above-mentioned complex mechanistic aspects might explain, at least in part, the highly controversial conclusions of epidemiological studies on breast cancer risk, with some authors reporting positive associations with specific POPs, but many others finding no evidence to support a causal relationship (Arrebola et al., 2015, Cassidy et al., 2005, Charlier et al., 2003a, Charlier et al., 2003b, Cohn et al., 2015, Demers et al., 2000, Demers et al., 2002, Gatto et al., 2007, Hoyer et al., 2001, Ibarluzea et al., 2004, Itoh et al., 2009, Laden et al., 2001, Lopez-Carrillo et al., 1997, Lopez-Carrillo et al., 2002, Lopez-Cervantes et al., 2004, Olaya-Contreras et al., 1998, Recio-Vega et al., 2011, Snedeker, 2001, Ward et al., 2000, Wolff et al., 2000a, Wolff et al., 2000b, Zheng et al., 1999a, Zheng et al., 1999b). Currently, there is no consensus on this issue, and discrepancies among studies may be in part attributable to methodological differences, e.g., in study design, target population (with distinct exposure backgrounds), and even the biological matrix utilized for exposure assessment (Artacho-Cordon et al., 2015), and also to the lack of research that takes account of the complex mechanistic aspects in the pathogenesis of breast cancer. In this regard, a report from the Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC) identified several gaps of knowledge in the relationship between chemical exposure and breast cancer, including: a) the role of the chemicals as direct carcinogens or effect modifiers; b) the relevance of exposures during critical windows of susceptibility; c) potential differential effects according to breast cancer subtype and sex; and d) potential protective factors against environmental pollutants (Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC), 2013).

The objective of this study was to evaluate associations between a set of cancer prognostic markers and exposure to a group of OCPs and PCBs, measured in both adipose tissue and serum samples from breast cancer patients.

Section snippets

Study population

The study population comprised 103 breast cancer patients described elsewhere (Artacho-Cordon et al., 2015). They were consecutively recruited between January 2012 and June 2014 among newly diagnosed women at San Cecilio University Hospital in the city of Granada (Southern Spain). All patients signed their informed consent to participate in the study, which was approved by the Ethics Committee of Granada (“Comité de Ética de la Investigación Biomédica de la provincia de Granada”).

Clinical data

Data on tumor

Results

Table 1 summarizes population characteristics. Briefly, the majority of the women were married and had schooling up to primary level. Median age and BMI were 51 yrs and 26.3 Kg/m2, respectively. POP detection rates and concentrations in this population were reported elsewhere (Artacho-Cordon et al., 2015) and have been included in as a figure in Supplementary Material. Briefly, median adipose tissue concentrations ranged from 44.71 ng/g lipid (PCB-180) to 194.34 ng/g lipid (p,p′-DDE), and

Discussion

This study describes associations between a set of breast tumor prognostic markers and POP concentrations quantified in two biological matrices from a sample of breast cancer patients, suggesting that human exposure to certain POPs (or mixtures of them) might influence the severity of breast cancer.

The associations found between these environmental contaminants in adipose tissue and the expression of some hormonal receptors might result from a POP-induced carcinogenic microenvironment that

Acknowledgements

The authors gratefully acknowledge technical assistance provided by Richard Davies. During this work, Dr JP Arrebola was first under a postdoctoral contract from the Junta de Andalucía, Spain (RH-0092-20013), and later under contract from the Instituto de Salud Carlos III, Spain (Miguel Servet Program CP15/00193). F Artacho-Cordón has a fellowship from the Spanish Ministry of Education (FPU12/02524). This study was supported in part by research grants from CIBER de Epidemiología, Instituto de

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