Non steroidal anti inflammatory drugs which include aspirin
Non-steroidal anti-inflammatory drugs, which include aspirin and ibuprofen, target COX-2 activity to inhibit inflammation. It has been shown that daily use of a nonsteroidal anti-inflammatory drugs is associated with reduced ER-positive breast cancer recurrence in obese and overweight women. More precisely, daily non-steroidal anti-inflammatory drug use was correlated with a 52% lower recurrence rate and a 28-month delay in time to recurrence (Bowers et al., 2014). A large prospective study conducted on women diagnosed with stages I, II, or III breast cancer confirmed that among women living at least 1 year after a breast cancer diagnosis, aspirin use 6–7 days/week was associated with a decreased risk of distant recurrence and breast cancer death (Holmes et al., 2010). Furthermore, COX-2 inhibitor use after diagnosis has been shown to reduce the incidence of bone metastases (Valsecchi et al., 2009). Given that obesity is associated with aromatase inhibitor resistance, the addition of a COX-2 inhibitor to aromatase inhibitor treatment may provide additional benefit for breast cancer patients as suggested by several clinical trials (Lustberg et al, 2011, Chow et al, 2008). Together, these data suggest that overweight and obese patients suffering from breast cancer may benefit from non-steroidal anti-inflammatory drug use. Inactivation of EP receptors is another therapeutic strategy in obesity-induced breast cancer. In vivo studies have shown that antagonism of the EP4 receptor reduced metastasis as compared with vehicle-treated controls in a murine model of metastatic breast cancer (Ma et al., 2006). Tumor cell proliferation was also directly inhibited by antagonists of either EP4 or EP1/EP2 receptors (Ma et al, 2006, Kundu et al, 2009), supporting the ER 50891 that EP receptor antagonists may be an alternative approach to the use of COX inhibitors. Downstream effectors of PKA and PKC pathways represent a myriad of other potential targets. For example, PGE2 induces the transcription factor JunD in a PKC-dependent manner (Chen et al., 2011). JunD then directly activates aromatase promoters I.3/PII by binding to the CRE motif in the promoter region. JunD knockdown by small interfering RNA markedly inhibited PGE2-induced aromatase mRNA and activity in cultured human breast adipose fibroblasts, suggesting that targeting JunD may potentially achieve a selective ablation of local aromatase expression in breast cancer tissue via specific inhibition of aromatase promoters I.3/II (Chen et al., 2011). Interestingly, a study has recently demonstrated that natural gut-hormones ghrelin and des-acyl ghrelin were able to specifically inhibit aromatase transcript expression and activity in adipose stromal cells under basal conditions and in PGE2-stimulated cells (Docanto et al., 2014), suggesting that mimetics of these natural compounds may be useful in the treatment of hormone-dependent breast cancer. Beneficial actions of dietary vitamin D on reducing the adverse effects of obesity towards breast cancer have also been recently highlighted (Swami et al., 2016). Authors have demonstrated that vitamin D treatment caused a delay in tumor appearance and inhibited tumor growth including by repressing aromatase and COX-2 expression and subsequently tumor-derived estrogen and PGE2 levels, but also by reducing expression of leptin receptors and inducing adiponectin signaling in obese mice. Vitamin D was also found to regulate the LKB1/AMPK pathway, contributing to an overall decrease in local estrogen synthesis in the obese mice (Swami et al., 2016). Activation of AMPK by the anti-diabetic drug metformin also leads to suppression of aromatase expression in human breast adipose stromal cells (Brown et al., 2010). Further studies demonstrated that these effects were specific to promoters I.3/PII (Samarajeewa et al., 2011). Metformin has been the focus of many cancer-related studies since the observation that diabetics on metformin were less likely to develop a number of cancers than those who weren't (Evans et al., 2005). It is therefore plausible that some of the anti-tumor effects of metformin are mediated via suppression of aromatase.