Academic journal article Environmental Health Perspectives

Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway

Academic journal article Environmental Health Perspectives

Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway

Article excerpt



In 2017, 26,300 women were diagnosed with breast cancer in Canada (Canadian Cancer Society's Advisory Committee on Cancer Statistics 2017). In the United States, it was expected that 252,710 new cases of breast cancer would be diagnosed in 2017 (American Cancer Society 2017). Of these cases, 83% were estrogen-receptor and/or progesterone-receptor positive (American Cancer Society 2017). In this type of cancer, increased local estrogen is produced, resulting in greater concentrations in the tumor microenvironment, which stimulates the proliferation of breast cancer epithelial cells (Ghosh et al. 2009; Yamaguchi and Hayashi 2009). Aromatase (CYP19) is a key enzyme in the biosynthesis of estrogens, as it is responsible of the final conversion of androstenedione to estrone, and testosterone to estradiol (Bulun et al. 2003). The CYP19 gene is expressed in a tissue-specific manner by the activation of various promoters located in the noncoding region of the gene. In the normal breast, CYP19 is expressed at low levels in fibroblast cells (stromal preadipocytes) and driven by the I.4 promoter (Simpson and Davis 2001).

In breast cancer, a series of events leads to the inhibition of I.4 promoter activity (Agarwal et al. 1996; Harada et al. 1993) and the activation of several promoters that are normally inactive in the stromal cells of the mammary gland, namely PII, I.3, and I.7 (Irahara et al. 2006; Subbaramaiah et al. 2012; Zhou et al. 1997). This unique switch in promoter usage results in an increase of overall CYP19 gene expression, aromatase catalytic activity, and subsequent estrogen biosynthesis. Moreover, malignant epithelial cells synthesize prostaglandin E2 (PG[E.sub.2]), which binds to its G-protein-coupled PG[E.sub.2] receptor to stimulate the production of cyclic AMP (cAMP), which results in increased CYP19 expression through activation of promoters PII and I.3 (Chen et al. 2007; Subbaramaiah et al. 2012). PG[E.sub.2] can also activate the orphan nuclear receptor homologue-1 (LRH-1), known to induce CYP19 expression in breast tissue (Zhou et al. 2005).

Increased levels of PG[E.sub.2], and other inflammatory factors such as TNF[alpha] and IL-11 in the tumor microenvironment only partially explain the promoter-switch in regulation of CYP19 expression that occurs in hormone-dependent breast cancer patients. Another potential contributor to the promoter-switch in CYP19 expression is the vascular endothelial growth factor (VEGF) receptor signaling pathway. The VEGF receptor (VEGFR) signaling pathway plays a central role in angiogenesis. More precisely, secretion of VEGF is associated with proliferation of vascular endothelial cells (Schneider and Sledge 2007). It has been demonstrated that VEGF and its receptors are overexpressed in breast cancer (Adams et al. 2000; Konecny et al. 2004). Furthermore, we know that VEGF-promotes angiogenesis and endothelial cell permeability by activating ERK 1/2 (MEK/MAPK1/3) (Breslin et al. 2003; Pai et al. 2001; Xu et al. 2008) and PLC/PKC (Cross and Claesson-Welsh 2001; Jiang et al. 2016).

Given the importance of aromatase in hormone-dependent breast cancer, understanding the regulation of the promoter-specific expression of CYP19 is paramount to assessing potential impacts of environmental contaminants on the development of this disease. Indeed, there is growing evidence that exposure to contaminants, such as pesticides, is a risk factor for hormone-dependent breast cancer (Cohn et al. 2007; Ibarluzea et al. 2004; Mathur et al. 2002; Xu et al. 2010). A lot of research has focused on effects of endocrine disruptors on the estrogen receptor (Bouskine et al. 2009; Roy et al. 2009; Rubin et al. 2001). The enzyme aromatase has been identified as a target for endocrine disrupting chemicals, including environmental pesticides (Sanderson 2006). However, we have little information on the roles that environmentally relevant levels of chemicals may play in the disruption of aromatase expression or activity. …

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