How White Adipose Tissue Inflammation Promotes Breast Cancer Development

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 growth3,. 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