Abstract 1514: The Warburg effect in stromal cells drives breast cancer cell plasticity via interleukin 6

Abstract

Abstract Background: Intra-tumoral heterogeneity is an emerging concept in breast cancer biology. This concept entails the notion that sub-populations within the tumor possess different biologic features and hence vary in sensitivity to therapies. The inhibition of estrogen receptor alpha (ER), a hormone based therapy (HT), is a successful therapy for luminal A breast cancer patients. However, HT resistance, due to a variety of factors such as the tumor microenvironment, plays a crucial role in breast cancer progression. Genetic alterations in the stromal fibroblasts, such as deficiency for the tumor-suppressors (TP53 and pRB) within the tumor microenvironment, are associated with poor prognosis in breast cancer. Hypothesis: We propose that stromal cells promote the intra-tumoral heterogeneity in luminal A breast cancer. We developed an in vivo model to study the crosstalk between bone marrow stromal cells (HS27) immortalized with human papilloma virus (HPV) E6 onco-protein and a luminal A breast cancer cell line, MCF-7. Results: Here we report that HS27 cells secrete high amounts of IL-6, which operates in an autocrine and paracrine fashion. Paracrine IL-6 from HS27 cells contributes to MCF-7 cancer cell dissemination and metastasis. Autocrine IL-6 drives anaerobic glycolysis (Warburg effect) and produces high levels of lactate and H+ from HS27 cells. High levels of IL-6 and lactate from the conditioned media of HS27 cells promote the expansion of a MCF-7 cells sub-population expressing high levels of lactate shuttle MCT-1 and low levels of ER. This cancer cell population exhibits invasive and metastatic potential. Finally, we show that HPV DNA positive breast cancer lesions are more biologically aggressive, and express higher levels of IL-6, than negative ones. Conclusion: This study highlights that tumor microenvironment stressors (viral infections and oncogenes) promote a complex metabolic crosstalk (anaerobic glycolysis and oxidative phosphorylation) between stroma and cancer cells, ultimately sustaining cancer progression. Grant support: DOD W81XWH-10-1-1033 to PS, NIH R01 CA87637 to JB, PRIN KTRN38 2008 to MB Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1514. doi:1538-7445.AM2012-1514