Crosstalk between NFkB and glucocorticoid signaling: a potential target of breast cancer therapy

Abstract

Breast cancer (BC) is an aggressive and high mortality cancer that can be classified into five molecular subtypes, based on gene expression profiling. The extreme heterogeneity poses difficulties for understanding and treating BC. Among many risk factors, inflammation plays a causal role in BC progression and recurrence, wherein NFkB and glucocorticoid receptor (GR) are critical transcription factors in regulating inflammation. NFkB is generally pro-inflammatory, and GR is anti-inflammatory, constituting a Yin-Yang mode in regulation. Thus, the crosstalk between these two transcription factors exerts even more important functions in determining the survival or apoptosis of BC cells. NFkB is widely involved in the initiation and progression of BC; its inhibitors are emerging as a potent primary or adjuvant therapy. On the other hand, glucocorticoids (GCs) are already used as neo-adjuvant and adjuvant therapies to treat various cancers with remarkable effects to induce apoptosis in leukemia and lymphoma. However, GCs unexpectedly promote cancer cell survival and induce chemo-resistance in BC. To understand this unique transcriptional interplay in BC, in this review we discuss the functions of NFkB and GR in BC development and progression by emphasizing their cross talk at cell signaling and protein interaction levels; and the future perspectives are proposed for the development of new therapeutic approaches for BC based on these signaling pathways.