Abstract P2-06-09: Inflammation promotes stem-like characteristics and increases stemness of breast epithelial cells
Authors: Jennifer Sims-Mourtada, Kimberly M Arnold, Lynn Opdenaker, Daniel Flynn
Journal: Cancer Research (2015)

Abstract Triple negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers and is more likely to affect younger women, women of African American descent, and BRCA1 mutation carriers. TNBC is typically an aggressive cancer and is defined as the absence of positive staining for estrogen (ER) and progesterone (PR) receptor, and a lack of amplification of HER2. Due to its receptor status, TNBC is insensitive to the conventional targeted treatment utilized in ER/PR/HER2 positive breast cancer leading to poor prognosis and early visceral metastasis with survival rates for women who relapse within 5 years of treatment being significantly lower than hormone receptor positive breast cancer. Therefore, understanding the mechanisms that drive the formation of TNBC can aid in determining targets to develop better treatment options. We investigated differences in the tumor microenvironment between TNBC and ER positive breast cancer patient tissue samples. Hematoxylin &amp; eosin stain of invasive ductal carcinomas revealed that TNBC patients had higher amounts of tumor infiltrating leukocytes compared to ER positive breast cancers. In premalignant breast cancer patients, ER negative ductal carcinoma in situ (DCIS) patients had significantly higher infiltrating leukocytes compared to ER positive DCIS indicating that inflammation may be a contributing factor in TNBC. Research on molecular profiling of TNBC has revealed that a subset of gene expression patterns are associated with the basal-myoepithelial cells rather than the luminal cells, however, previous evidence indicates that TNBC arises from luminal progenitors which undergo an abnormal conversion to basal-like progenitors with enhanced growth and survival promoting characteristics. We propose this conversion occurs due to the presence of inflammatory signals early in tumor development which trigger a cascade of events that leads to acquisition of a basal-like phenotype in luminal progenitor cells and upregulation of stem-like properties, resulting in the formation of basal-like breast cancer/TNBC. Treatment of non-malignant breast epithelial cells with IL-6 increased sphere-forming efficiency under stem cell growth promoting conditions and an inhibitor of the IL-6/STAT3 pathway decreased ALDH enzymatic activity as measured by Aldefluor assay. Also, treatment with IL-6 downregulated the luminal marker, epithelial specific antigen (ESA), and increased the expression of the myoepithelial marker, CD49f, on the cell surface of non-malignant breast epithelial cells, indicating an increase in the basal-like cell population and a loss of the luminal cell population. Therefore, inflammation appears to be a common feature in TNBC compared to ER positive breast cancer and the presence of an inflammatory stimulus in the breast may promote the conversion of luminal to basal-like cells, promoting the upregulation of stem-like properties and development of TNBC. These data suggest that anti-inflammatory drugs could potentially be used to inhibit these events from occurring in the development of TNBC, leading to decreased tumor growth and better treatment options. Citation Format: Jennifer Sims-Mourtada, Kimberly M Arnold, Lynn Opdenaker, Daniel Flynn. Inflammation promotes stem-like characteristics and increases stemness of breast epithelial cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-09.