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.

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

“…Since chemoresistance of TNBC is multifaceted, based on the interplay of drug efflux [67], apoptosis [68,69], cancer stem cell phenotype [17], tumor microenvironment [70], and multiple signaling pathways [71], the mechanism of chemoresistance in TNBC has to be analyzed under many different aspects. In the present study, characteristics of BCSCs under chemotherapeutic stress were analyzed.…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…Their treatment depends on cytotoxic taxane-, anthracycline-, and platinum-based regimens that target cell-cycle progression. In approximately 20% of these patients, tumors will completely regress after such therapy (complete pathological response), but for those patients that do not achieve this level of response, the risk of reoccurrence and death from metastases are many fold more than for those with hormone-positive cancers [9,10]. Overall, 90% of breast cancer patients who develop metastatic disease become resistant to their chemotherapy regimens [11].…”

“…Despite the high heterogeneity and a plethora of molecular signatures, there are common mechanisms of chemotherapy resistance in triple-negative breast cancers, which have also become recognized in recent years to be associated with treatment failure against hormonal and HER2/neu targeted treatments [10,12]. By no means exhaustive, three of these mechanisms of interest in breast cancer research are ATP-binding cassette (ABC) transporters, cancer stem cells, and microRNAs.…”

Iron Oxide Nanoparticle-Induced Autophagic Flux Is Regulated by Interplay between p53-mTOR Axis and Bcl-2 Signaling in Hepatic Cells

“…In fact, Bcl-2 shows as well anti-autophagic activity by stabilizing lysosomal membrane and preventing lysosomal destabilization [100,101]. As a result, cancer cells, that express elevated Bcl-2 levels, are more chemoresistant to the standard treatments that activate either apoptosis or autophagic cell death [102,103]. Not surprisingly, we found that HepG2 cells upon NP treatment did not exhibit lysosomal dysfunction (Figure 5g) and destabilization (Figure 5f and Supplementary Figure S6).…”