Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer-How We Can Rise to the Challenge

Abstract

Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC's high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies.

Keywords: ABC transporters; Triple-negative breast cancer; apoptosis; cancer stem cells; chemoresistance; hypoxia; microRNA; molecular subtypes; receptor tyrosine kinases; signaling pathways.

Figure 1

Cancer stem cell theory. Chemotherapy reduces bulk tumor burden but resistant cancer stem cells (CSCs) survive and are able to drive tumor recurrence. Specifically targeting CSCs is necessary to achieve stable tumor remission.

Figure 2

Overview of developmental pathways and their potential inhibitors in triple-negative breast cancer (TNBC). TGF-β (transforming growth factor-beta), Notch, Wnt/β-catenin and hedgehog (Hh) pathways all have crucial roles in initiation, progression, CSC maintenance, metastasis, and chemoresistance of TNBC. A number of inhibitors have recently been developed to target these pathways. Inhibitors are shown in red.

Figure 3

Role of hypoxia in tumor chemoresistance. Hypoxia induces numerous mechanisms that interfere with cytotoxic drugs and hinder their success.

Figure 4

Targeting apoptotic pathways in TNBC. Cancer cells contain two pathways that can trigger apoptosis: intrinsic, that is activated in response to cellular damage, and extrinsic, which is mediated by death receptor activation. Both are potential targets for TNBC treatment.

Figure 5

Targeting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); PI3K-AKT-mTOR (PAM); Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways and receptor tyrosine kinases in TNBC. Select inhibitors are shown in red.