Abstract P4-04-03: Obesity-induced EMT in luminal A breast cancer cells

Abstract

Abstract Introduction: Obesity is associated with a worse prognosis in breast cancer, including the less aggressive ER+ luminal A subtype, but the mechanisms by which it promotes disease progression are unclear, making treatment difficult. Obese breast cancer patients have a higher risk of a more aggressive disease compared to lean patients, which is associated with treatment resistance and metastasis. The mechanisms promoting obesity-driven metastasis are not understood, but several studies have indicated that obesity is associated with a “stem-like” phenotype. A “reprogramming” occurs, transforming stationary, epithelial cells to motile, malignant cells that exhibit a more aggressive phenotype than their stromal counterparts. Our data suggest that in vitro exposure of luminal A breast cancer cells to obese conditions may induce an epithelial to mesenchymal transition (EMT), which is characterized by a more stem-like phenotype, resistance to treatment (chemo, hormone and radiation), as well as greater metastatic potential. This has let us to hypothesize that one critical mechanism by which obesity promotes a more aggressive disease is through inducing an EMT reprogramming, resulting in a more stem-like phenotype. Methods and Results: Both in vitro and translational approaches will be done to determine if obesity induces epigenetic reprograming associated with a more stem-like phenotype. MCF-7 ER+ breast cancer cells exposed to 2% sera from obese (BMI ≥ 30) postmenopausal women demonstrated a significant increase in expression of both SNAIL1 and TWIST transcription factors (9-fold and 4-fold, respectively) which are implicated in EMT and potentially stem-cell programming, compared to those exposed to sera from lean women. Current studies are underway to determine if this is observed in other ER+ luminal A cell lines, including T47D, and whether induced changes in these transcription factors results in changes in signaling pathways associated with EMT, including TGFβ, which can activate the PI3K–AKT, ERK MAPK, p38 MAPK and JNK pathways and WNT signaling, which promotes EMT by stabilizing β-catenin. Additionally, the luminal A cell lines will be assessed for changes in other factors known to modulate breast cancer cell programming, including KLF4, OCT4, SOX2, and NANOG. Conclusions: Our earlier studies have demonstrated that obesity promotes a more aggressive disease even in luminal A disease. The mechanisms for this remain unclear. Our exciting preliminary findings suggest that obesity might induce a reprogramming of the luminal A well-differentiated cell to a more stem-like phenotype. Our results will lay an important foundation for understanding how obesity modulates breast cancer disease progression, whether this programming may provide therapeutic target to improve response and overall survival in the obese patient. Citation Format: Hayden A, Quach D, Galvan G, Patodia R, Brenner A, deGraffenried L. Obesity-induced EMT in luminal A breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-04-03.