Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1

Abstract

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a −3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.

Prospect of natural products in glioma: A novel avenue in glioma management

“…Glyceollin has shown to reduce invasion and migration properties of letrozole resistant breast cancer cells via its inhibitory effect on ZEB1. In vivo study also reveals lower ZEB1 expression in tumors of glyceollin‐treated animals (Carriere et al, ). This mechanism of glyceollin might be useful in glioma therapy.…”

Phytochemicals: Current strategies for treating breast cancer (Review)

“…There have been advancements in chemotherapeutic agents over the past decade; however, there is still an urgent need to overcome drug resistance. Numerous studies have focused on phytochemicals, which are nonnutritive plant chemicals that have disease-protective or -preventive properties (12)(13)(14). These chemicals are non-essential nutrients, meaning they are not required by the human body for sustaining life (15).…”

“…Due to the inherently resistant nature of BCSCs and their involvement in metastasis, it is increasingly imperative to develop therapies able to directly target these cells. While it is understood that certain soy phytochemicals, including glyceollins, target the EMT (14,73) (Fig. 2), their impact on BCSCs remains unclear.…”

The 2014 Minority Health and Health Disparities Grantees’ Conference

“…Carriere and collaborators [2] studied the role of glyceollin I in the treatment of Letrozole resistant breast cancer. They found that letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression by about 4 fold, while glyceollin I treatment caused a 4-fold reduction.…”