br Dysregulated aromatase expression the link
Dysregulated aromatase expression: the link between obesity and breast cancer Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, influencing the local production and bioavailability of estrogens (Morris et al, 2011, Subbaramaiah et al, 2012). Bowers et al. have used an in vitro model where a co-culture of MCF-7 breast cancer MK-8745 and pre-adipocytes were exposed to pooled serum from obese or normal weight postmenopausal women. They observed that pre-adipocyte aromatase expression was as much as 89% greater following culture in conditioned media from MCF-7 cells exposed to obese compared to normal weight sera (Bowers et al., 2015). Consistently, an in vivo study has reported an increased aromatase expression and activity (up to 3-fold) in mammary glands of diet-induced obese mice (Subbaramaiah et al., 2011). Clinical studies have translated these experimental observations to women by showing that elevated BMI is associated with high aromatase expression and activity in breast tissue (Brown et al, 2017, Morris et al, 2011, Subbaramaiah et al, 2012, Purohit et al, 1995). In the study conducted by Morris and colleagues, breast tissue was obtained from 30 women who underwent breast surgery. Levels of aromatase mRNA and activity were determined in breast tissue from each of the 30 subjects and correlated with BMI. Elevated BMI was shown to be associated with increased amounts of aromatase mRNA and activity in breast tissue (Morris et al., 2011). These findings are consistent with the results of previous studies which found higher levels of aromatase in thigh and abdominal adipose tissue in obese versus lean individuals (Bulun and Simpson, 1994). Moreover, a recent study of 161 women also demonstrated that obesity had more pronounced effects on breast aromatase expression in post-versus premenopausal women, providing additional evidence for the importance of the local biosynthesis of estrogens in the context of obesity and breast cancer in these women (Brown et al., 2017). The demonstration of the crucial role of dysregulated local aromatase expression in breast carcinogenesis was supported by several animal studies. With an aromatase-transgenic mouse model, authors have showed that overexpression of aromatase alone was sufficient to induce and maintain early preneoplastic and neoplastic changes in mammary gland in the absence of circulating estrogens and these changes can be abrogated using aromatase inhibitors (Tekmal et al, 1999, Kirma et al, 2001). Given the recognized importance of aromatase activity in both the development and progression of hormone-dependent breast cancer, work from several laboratories has focused on mechanisms supporting the induction of aromatase expression in obese women. The first reason explaining this increased expression of aromatase in the breast of obese women may simply be a matter of altered cell composition. The hyperplasia of adipose tissue observed during weight gain in obese women increases number of adipose cells, leading to an increase number of pre-adipocytes expressing aromatase in the breast (Bulun et al, 2012, Jo et al, 2009). Secondly and more importantly, dysfunctional breast adipose tissue in obese women releases a different profile of adipokines with elevated levels of pro-inflammatory factors, including prostaglandin E2 (PGE2), interleukin-1β (IL-1β), IL-6 and TNF-α, causing chronic in-breast inflammation (Pierce et al, 2009, Monteiro and Azevedo, 2010). This inflammation is widely considered to underpin breast carcinogenesis and provide the molecular key to understanding obesity-induced aromatase expression (Subbaramaiah et al., 2012).
Inflammation: the missing connection in the obesity-aromatase-breast cancer triad In the process of stocking excess lipids, the abnormal expansion of white adipose mass via hyperplasia and/or adipocyte hypertrophy results in cellular stress, adipose tissue fibrosis and local hypoxia (Rutkowski et al., 2015). This, in turn, is associated with adipocyte dysfunction or death, and with the initiation of an inflammatory response (Lee et al, 2014, Michaud et al, 2012). Altered production of pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), by adipocytes leads to the recruitment and local invasion of immune cells, particularly macrophages (Kanda et al., 2006).