Molecular Biology Mechanisms and Emerging Therapeutics of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is conventionally characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), accounting for approximately 15-20% of all breast cancers. Compared to other molecular phenotypes, TNBC is typically associated with high malignancy and poor prognosis. Cytotoxic agents have been the mainstay of treatment for the past few decades due to the lack of definitive targets and limited therapeutic interventions. However, recent developments have demonstrated that TNBC has peculiar molecular classifications and biomarkers, which provide the possibility of evolving treatment from basic cytotoxic chemotherapy to an expanding domain of targeted therapies. This review presents a framework for understanding the current clinical experience surrounding molecular biology mechanisms in TNBC (Figure 1). Including immunotherapy, polymerase (PARP) and PI3K/AKT pathway inhibitors, antibody-drug conjugates, and androgen receptor (AR) blockade. Additionally, the role of miRNA therapeutics targeting TNBC and potential strategies targeting cancer stem cells (CSCs) are discussed and highlighted. As more and more treatments arise on the horizon, we believe that patients with TNBC will have a new sense of hope.

Keywords: PI3K/AKT pathway inhibitors; antibody-drug conjugates; cancer stem cells; miRNA therapeutics; triple-negative breast cancer.

Figure 1

Current immunotherapy and combination therapeutic strategies for the treatment of triple-negative breast include killing of cancer cells, prevent cancer cell antigen release, promote T-cell infiltration into tumors and activate immune system. The main agents include chemotherapy, PD-1/L1 inhibitors, AKT inhibitors, PARP inhibitors and MEK inhibitors.

Figure 2

In 2011, Lehmann et al categorize TNBC into six different subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). In 2015, Burstein identified four distinct TNBC subtypes: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immunosuppressed (BLIS), and basal-like immune-activated (BLIA). In 2016, Liu and colleagues developed a novel TNBC classification system that integrates the expression profiles of both mRNAs and lncRNAs. The system divided TNBC subtypes into four subtypes: immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal-like (MES), basal-like and immune suppressed (BLIS).