Triple Negative Breast Cancer Heterogeneity and Tumour Microenvironment- based Model Systems' Focus on Druggable Targets.

Abstract

Fifteen to twenty percent of all cases of breast cancer are TNBC (triple negative breast cancer) and exhibit heterogenic features due to their diverse molecular characteristics. Additionally, their aberrant cell cycling behavior contributes to their metastatic capabilities and aggressive nature. TNBC is the only molecular subtype, which lacks the expression of hormone receptors, like estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). Hence, it is recalcitrant to hormone therapy. Also, the complex and evolving tumour microenvironment (TME) comprises blood vessels, stromal cells, immune cells, metabolic factors, extracellular matrix (ECM), and an integrated perspective of their interconnections as well as their variability with respect to TNBC progression needs to be comprehended for biomarker/druggable target(s) development and/or their validation. Such TME-based model systems can help us understand the relationship between the different TME components that affect tumour growth and metastasis. This review also catalogs biomarkers and TNBC behaviour within the TME. Also, this review discusses and analyses models that replicate various tumour subtypes that can be correlated with variability in treatment responses, thereby facilitating a better understanding of TNBC heterogeneity. Thus, by identifying biomarkers and constructing model systems, we can augment efforts to overcome treatment failure and poor outcomes in TNBC patients. These subtype-specific TNBC model systems, mirroring the intricacies of the TME, have the potential to provide a feasible and innovative approach to target TNBC cells. This review will facilitate the ongoing global efforts to develop efficacious and safe "tailor-made" drugs for TNBC patients.