Christine Yang

Introduction 80% of all breast cancers are ER-positive, meaning the cancer cells contain receptors for estrogen and proliferate in response to estrogen². An increased body mass index (BMI) potentiates the risk for ER-positive breast cancer development due to the increase percentage of white adipose tissue in the body¹_.  Studies demonstrate white adipose tissue growth creates hypoxic conditions in breast tissue, which induces expression of hypoxia inducible factors (HIFs) that promotes release of pro-tumorigenic inflammatory mediators such as COX-2 derived Prostaglandin E2 (PGE-2). The presence of WAT inflammation is characterized by the presence of dying adipocytes surrounded by macrophages that form a crown-like structure of the breast (CLS-B)⁵. The macrophages release pro-inflammatory mediators such as IL-6 and COX-2 derived prostaglandin E2. This stimulates the cAMP to PKA signal transduction pathway that enhances aromatase transcription. Aromatase is the rate-determining enzyme that catalyzes the conversion of androgens to estrogen for tumor cells to utilize for growth^3,. Methods. THP-1 human macrophages were treated with stearic acid to create a conditioned medium (CM). Human visceral preadipocytes were treated with this CM and levels of PGE2, cAMP, and protein kinase A activity were quantified using EIA kits. The breast tissue was obtained from 30 women undergoing mastectomies and categorized by BMI (Normal: 18.5-24.9, overweight 25-29.9, obese >30)³. The tissues were stained with CD68, a macrophage marker to identify CLS-B. Light microscopy was used to assess for evidence of CLS-B⁵. In another study, MCF-7 breast cancer cells and pre-adipocytes were treated with conditioned medium from normal weight (N-CM; BMI 18.5-24.9) and obese (OB-CM; BMI >30.0) postmenopausal women. Levels of COX-2, PGE-2, and aromatase activity were assessed⁴. Results Studies demonstrate an increased presence of CLS-B in overweight/obese patients compared to normal weight patients⁵. Levels of COX-2, PGE-2, cAMP and PKA were elevated in the breast tissue of overweight/obese patients compared to normal weight patients⁴. In a different study, THP-1 cells treated with stearic acid showed a 7x increased in PGE-2 production in pre-adipocytes treated with OB-CM⁴. Furthermore, pre-adipocytes treated with OB-CM had increased levels of cAMP, PKA, and aromatase activity compared to cells treated with N-CM. PGE-2 levels in MCF-7 cells cultured on OB-CM was 12x higher compared to MCF-7 cells cultured in N-CM⁴. Conclusions Increased WAT growth promotes inflammation, leading to formation of CLS-B whose macrophages secrete pro-tumorigenic inflammatory mediators that activate the cAMP signal transduction pathway to increase aromatase expression.

1.  Breast Cancer. U.S. Breast Cancer Specifics. http://www.breastcancer.org/symptoms/understand_bc/statistics. Accessed May 10, 2018. WebMD. Types of Breast Cancer https://www.webmd.com/breast-cancer/guide/breast-cancer-types-er-positive-her2-positive#1. Accessed May 18, 2018
2. Subbaramaiah K, Morris PG, Zhou XK, et al. Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2012;2(4):356-65.
3. Bowers LW, Brenner AJ, Hursting SD, Tekmal RR, Degraffenried LA. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production. Breast Cancer Res Treat. 2015;149(1):49-57.
4. Iyengar NM, Zhou XK, Gucalp A, et al. Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer. Clin Cancer Res. 2016;22(9):2283-9. 10.1158/1078-0432.CCR-15-2239