Abstract B01: Immune cell infiltrates differ by obesity in tumor and adjacent normal breast tissue in African American women with triple-negative breast cancer
Authors: Shaik Asra N. , Boerner Julie L. , Cote Michele L. , Dyson Gregory , Ali-Fehmi Rouba , Bandyopadhyay Sudeshna , Purrington Kristen S. 
Published: August 2018

Introduction: Obesity is a risk factor for breast cancer, including the more aggressive triple-negative (TN) subtype, but the relevance of obesity to prognosis remains unclear. Unlike other subtypes, triple-negative breast cancer (TNBC) is not hormonally responsive and is characterized by a lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. Thus, obesity-related development of TN tumors is unlikely to rely on the peripheral aromatization of androgens to estrogens in fat. Chronic, low-grade inflammation elicited by obesity could increase risk of TNBC. Here we sought to assess which mechanisms mediate obesity’s effect on normal tissue and TN tumors using a gene expression approach. Because African American women are more likely to be obese and twice as likely to develop TNBC compared to white women, understanding the mechanisms of obesity-related risk of TNBC is critical for this high-risk group.

Methods: We performed whole-genome expression profiling on formalin-fixed, paraffin-embedded samples from 104 African American women with TNBC (59 tumor, 45 adjacent normal). Body mass index was obtained by medical record abstraction, and women with BMI at least 30 kg/m2 were classified as obese. Gene Ontology (GO) was used to identify biologic processes enriched in differentially expressed genes by obesity status in tumors and adjacent normal tissue (p-value&lt;0.05). CIBERSORT was used to estimate proportions of 22 immune cell subtypes using expression profiles, and differences in median immune cell proportions by obesity status were evaluated.

Results: 28 (47%) TNBC tumor and 29 (64%) adjacent normal samples were from obese women. Among genes more highly expressed in tumors from obese compared to nonobese women, GO analysis revealed enrichment for proinflammatory processes involving regulation of immune system, activation of immune responses, leukocyte activation, and neutrophil activation (FDR-corrected p-value &lt;0.05). In contrast, GO analysis showed that genes in pathways related to B and T cell activation, cytokine production, regulation of immune system, and immune response (all FDR-corrected p &lt;0.05) were downregulated in adjacent normal tissue from obese compared to nonobese women. Tumors from obese women exhibited a proinflammatory environment with increased levels of CD4 T memory resting cells, resting mast cells, and neutrophils, and reduced levels of regulatory T cells, resting dendritic cells, and activated mast cells (p &lt; 0.1). We also found reduced proportions of naïve B cells, CD4 T memory resting cells, and M1 macrophages but an increased proportion of resting mast cells in the adjacent normal tissue of obese women compared to nonobese women (p&lt; 0.1).

Conclusions: Obesity modifies the immune cell environment present not only in TN tumors but also in the surrounding normal tissue. Obesity promotes a more proinflammatory setting within TN tumors, and in contrast, an anti-inflammatory setting in normal tissue adjacent. These findings may have important implications for understanding how obesity influences TNBC risk and prognosis, particularly among African American women who are at high risk for both.

Citation Format: Asra N. Shaik, Julie L. Boerner, Michele L. Cote, Gregory Dyson, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Kristen S. Purrington. Immune cell infiltrates differ by obesity in tumor and adjacent normal breast tissue in African American women with triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B01.