Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population

Abstract

Multiple studies have demonstrated that obesity is associated with a worse outcome for all breast cancer subtypes and that obese breast cancer patients do not respond as well as normal weight patients to aromatase inhibitor treatment and chemotherapy. While a number of mechanisms have been proposed to explain this link, recent studies have provided evidence that elevated local cyclooxygenase-2 (COX-2) expression and the resulting increase in prostaglandin E2 (PGE2) production may play an important role. COX-2 upregulation in breast tumors is associated with a poor prognosis, a connection generally attributed to PGE2’s direct effects on apoptosis and invasion as well as its stimulation of pre-adipocyte aromatase expression and subsequent estrogen production. Research in this area has provided a strong foundation for the hypothesis that COX-2 signaling is involved in the obesity-breast cancer link, and further study regarding the role of COX-2 in this link is warranted.

PTGS2 polymorphism rs689466 favors breast cancer recurrence in obese patients

“…Moreover, the negative impacts of rs689466 variant genotypes or haplotype *4 on disease-free survival of breast cancer patients were dependent on the menopausal status, being detected only in postmenopausal women. Such findings appear to reinforce the role of local aromatase induction and the consequent estradiol production by breast adipose tissue after menopause, which can be induced by elevated COX2 and PGE2 in inflamed breast tissue of obese women (Bowers & deGraffenried 2015).…”

“…Such deleterious effect of rs689466 on prognosis, however, was valid only for obese patients, suggesting that its action may depend on the availability of stimulating factors, probably released within the obesity-related inflammatory process. Accordingly, obesity has been associated with increased circulating levels of several growth factors, cytokines and adipokines, including interleukin-6, an inflammatory Endocrine-Related Cancer cytokine secreted by both immune cells and adipocytes, which have been shown to promote PGE2 production via its effects on COX2, resulting in elevated aromatase levels and estrogen production in the breast tissue (Bowers et al 2015). Moreover, the negative impacts of rs689466 variant genotypes or haplotype *4 on disease-free survival of breast cancer patients were dependent on the menopausal status, being detected only in postmenopausal women.…”

“…Interestingly, the deleterious effect of rs689466 variant genotypes or haplotype *4 on prognosis was observed irrespective of tumor subtype. Although luminal tumors have lower progression rates, they are considered more likely to have its prognosis affected by obesity in postmenopausal women, possibly because they express ER and might be more sensitive to increased aromatase expression and local estradiol release (Bowers & deGraffenried 2015). Nevertheless, triple-negative tumors have been shown to express high levels of COX2, which correlate with poor survival outcomes (Tian et al 2017).…”

The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance

“…Moreover, selective COX-2 inhibition has been suggested to be potentially capable of preventing or delaying diabetic neuropathy [14]. In clinical studies, Laura et al demonstrated that, in the breast tissue of obese women, a higher concentration of circulating cytokines promotes greater macrophage COX-2 expression and produces more PGE 2 [15]. These observations indicate that COX-2-mediated inflammation substantially contributes to relevant complications in subjects with metabolic syndrome and diabetes, further strengthening the importance of COX-2 activation in the development of obesity and obesity-related complications.…”

Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient’s Body Mass Index

“…NSAIDs are acting on biological processes altered both by primary tumor surgery, as described above, and by adiposity. For instance, it has been suggested that adiposity could induce COX-2 expression by the macrophages and tumor cells (19) and promote angiogenesis (20)(21)(22). We therefore hypothesized that breast cancer patients with an elevated BMI would have an increased benefit from intra-operative NSAIDs.…”