NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions

Abstract

Obesity is associated with a worse breast cancer prognosis and elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the proinflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. This study demonstrates that daily use of a nonsteroidal anti-inflammatory drug (NSAID), which inhibits COX-2 activity, is associated with reduced estrogen receptor a (ERa)-positive breast cancer recurrence in obese and overweight women. Retrospective review of data from ERa-positive patients with an average body mass index of >30 revealed that NSAID users had a 52% lower recurrence rate and a 28-month delay in time to recurrence. To examine the mechanisms that may be mediating this effect, we conducted in vitro studies that utilized sera from obese and normal-weight patients with breast cancer. Exposure to sera from obese patients stimulated greater macrophage COX-2 expression and PGE2 production. This was correlated with enhanced preadipocyte aromatase expression following incubation in conditioned media (CM) collected from the obese-patient, sera-exposed macrophages, an effect neutralized by COX-2 inhibition with celecoxib. In addition, CM from macrophage/preadipocyte cocultures exposed to sera from obese patients stimulated greater breast cancer cell ERa activity, proliferation, and migration compared with sera from normal-weight patients, and these differences were eliminated or reduced by the addition of an aromatase inhibitor during CM generation. Prospective studies designed to examine the clinical benefit of NSAID use in obese patients with breast cancer are warranted. Cancer Res; 74(16); 4446-57. Ó2014 AACR.

Obesity, Inflammation, and Cancer

“…Thus, approaches that attenuate adipose inflammation are likely targets for therapeutic intervention. Indeed, attenuation of systemic inflammation by NSAID administration is associated with reduced risk of obesity-related cancer, especially breast cancer (184)(185)(186), indicating that inflammation plays a prominent role. More investigation is needed to identify key inflammatory mechanisms and targets for more effective anti-cancer therapy.…”

Platelets at the interface of thrombosis, inflammation, and cancer

“…by guest www.bloodjournal.org From large patient datasets supports the anticancer effect of aspirin. [87][88][89][90] Thus, the topic has once again gained interest, and major questions surround the molecular basis of the benefit and the role played by of the platelet. 91 Aspirin directly inhibits cellular cyclooxygenase enzymes COX-1 and COX-2 and the production of prostaglandins.…”

Breast Cancer and Its Relationship with the Microbiota

“…For instance, one postulated inflammation-related mechanism for breast cancer is upregulation of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE), which results in increased aromatase expression in adipose tissue and increased conversion of androgen precursors to estrogens [77,78]. In this regard, the use of some non-steroidal anti-inflammatory drugs has been associated with a reduced risk of estrogen receptor (ER)-positive BC incidence or recurrence [79,80,81,82,83,84,85]. …”