A commentary on ‘Leveraging diverse cell-death patterns to predict the prognosis and drug sensitivity of triple-negative breast cancer patients after surgery’

Dear Editor,

Breast cancer is the most common malignancy diagnosed in women worldwide, with more than 2 million cases reported in the Global Cancer Observatory in 2018¹. With hormone receptor immunohistochemistry (IHC) stains of less than 1% for oestrogen and progesterone and the absence of HER2 protein overexpression or HER2 gene amplification (or both), triple-negative breast cancer (TNBC) accounts for 12–17% of all breast cancers. TNBC is of particular interest due to its heterogeneous nature in response to chemotherapy. Unlike other breast tumours, signature targets lack TNBC, causing high morbidity and mortality. Diverse programmed cell death (PCD) patterns play an important role in tumour progression, which has the potential to be a prognostic and drug sensitivity indicator for TNBC after surgery². Zou et al.³. established a novel indicator, the cell death index, to predict the efficacy of therapeutic interventions and prognosis with regard to TNBC. The results indicated that the PCD-related gene signature is a practical prognostic predictor for postoperative TNBC patients, which can make a notable difference in the assessment of clinical outcomes.

Cell death may occur when the damage is severe and the repair response is unable to provide protection or recovery, or it can be due to self-orchestration. Like other cell deaths, tumour cell death can occur programmed and accidentally, depending on the signalling pathway. PCD closely depends on tightly regulated intracellular signal transduction pathways, whereas accidental cell death is referred to as non-PCD due to unexpected cell injury. PCD can be further divided into apoptotic cell death and non-apoptotic cell death based on morphological characteristics and molecular mechanisms. Apoptosis preserves cell membrane integrity and happens in a caspase-dependent manner. On the other hand, non-apoptosis cell death occurs by membrane rupture and it is caspase-independent.

Apoptosis is triggered through two major pathways: an intrinsic and extrinsic pathway. The extrinsic pathway is triggered by death receptors (e.g. tumour necrosis factor), which are transmembrane proteins expressed on the cell surface, whilst the intrinsic pathway is mediated by mitochondria-released proteins (e.g. B-cell lymphoma 2 protein family). The morphological changes exhibited by apoptotic cells, which include cell blebbing and shrinkage, nuclear fragmentation, chromatin condensation, and fragmentation and formation of apoptotic bodies, are well characterised and can be observed via various imaging techniques. Apoptosis as a potential therapeutic target in breast cancer was widely investigated.

Autophagy allows cells under stress to regain control of their damage by a monitored delivery of cellular materials to lysosomes for recycling and degradation⁴. Three forms of autophagy have been identified, macro-mediated, micro-mediated and chaperon-mediated autophagy. Autophagy is a survival pathway of cancer cells exposed to genotoxic stress and activated by oncogenic signals. Many oncogenic proteins, such as class I phosphatidylinositol 3-kinase (PI3KCI), protein kinase B (AKT), mammalian target of rapamycin (mTOR), Bcl-2 and mitogen-activated protein kinases (MAPKs), may suppress autophagy, while others, including PI3KCIII, death-associated protein kinases (DAPKs), Beclin-1 and Bax-interacting factor 1 (Bif-1), promote it^5,6. A drug that can selectively target tumour cells is highly desirable in cancer treatment. Cancer involves multiple pathways with many protein receptors that are intertwined in their roles, thus creating a complex disease. These protein receptors are usually targeted to cause cell death, including autophagy. Although a lot of progress in this area of research has been made, many protein receptors’ functions are yet to be fully understood.

The main goal of cancer therapy since the 1990s, when PCD became a therapeutic strategy, has been to selectively eliminate tumour cells. Initially, apoptosis, as a drug target, gained tremendous support from the scientific community, as pivotal knowledge was gained on the mechanism leading to the cell death response. Although the concept of autophagy was coined in the 1960s, the ‘double-edged sword’ role played by autophagy in tumour progression continues to serve as a promising tool for anticancer therapy. Autophagy and apoptosis display a complex relationship in inducing cell death, and the preclinical data on small molecules targeting PCD shows encouraging progress. The emerging multidisciplinary approach in identifying lead compounds and target validation will provide potential therapeutic strategies in treating TNBC.

Ethical approval

This is a commentary, ethical approval is not required.

Consent

None.

Sources of funding

This research received grant from horizontal project of Jinzhou Medical University (STC-2S21094).

Author contribution

J.L.: writing and J.Y.: study design.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

None.

Guarantor

Jing Yang.

Data availability statement

Data are publicly available.

Provenance and peer review

None.