Breast Cancer: Ubiquitin-Specific Proteases in Cell Death Regulation

A new review draws attention to the pivotal role of ubiquitin-specific proteases (USPs) in regulating programmed cell death (PCD) in breast cancer (BC), the most common form of cancer among women. Despite significant strides in treatment, BC remains a major global health challenge, with issues such as treatment resistance and metastasis continuing to hinder progress. This article offers an in-depth exploration of how the processes of ubiquitination and deubiquitination, controlled by USPs, impact key cell death pathways that are essential to cancer progression and response to therapy (1^✔ ✔Trusted Source
Role of ubiquitin-specific proteases in programmed cell death of breast cancer cells

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Balancing Cell Death and Survival in Breast Cancer Therapy Resistance

The intricate ubiquitin-proteasome system (UPS) plays a vital role in maintaining cellular homeostasis, determining the fate of apoptotic, autophagic, necroptotic, ferroptotic, and pyroptotic pathways. By selectively modulating proteins involved in these pathways, USPs contribute to either promoting or inhibiting cancer cell survival. The review explores the dual role of PCD in BC, where certain forms of cell death act as a defense mechanism, while others enhance tumor growth and resistance to therapy.

Apoptosis, the most studied form of PCD, is closely linked to tumor suppression. However, BC cells often develop resistance to apoptotic signals, enabling uncontrolled proliferation. USPs such as USP22 and USP7 regulate key proteins like c-Myc and p53, influencing apoptosis in BC. Similarly, autophagy, a mechanism for cellular self-digestion, has a paradoxical role in BC, either inhibiting or promoting tumor survival. The review discusses how USP8 and USP13 influence autophagy by regulating Beclin1 and p62/SQSTM1, potentially affecting therapeutic outcomes.

Emerging Non-Apoptotic Pathways in Cancer Therapy

Emerging non-apoptotic PCD pathways such as ferroptosis and pyroptosis have garnered attention for their potential in cancer therapy. Ferroptosis, a form of iron-dependent cell death, has been identified as a promising target in triple-negative breast cancer (TNBC). The review highlights the role of USP7 and USP35 in ferroptosis regulation, underscoring the therapeutic possibilities of manipulating iron metabolism and oxidative stress. Pyroptosis, an inflammatory cell death pathway, is also examined, with a focus on USP48 and gasdermin E (GSDME), which contribute to immune responses and tumor suppression.

Beyond their influence on PCD, USPs play a role in tumor metastasis and drug resistance, presenting new challenges and opportunities for targeted therapy. The review emphasizes the need for further investigation into the crosstalk between USPs and PCD mechanisms, particularly in necroptosis and anoikis, which are less understood but critical in BC progression.

By unveiling the complex interactions between ubiquitination, cell death pathways, and cancer biology, this review lays the foundation for novel therapeutic strategies.

Reference:

1. Role of ubiquitin-specific proteases in programmed cell death of breast cancer cells - (https://www.sciencedirect.com/science/article/pii/S2352304224001387?via%3Dihub)

Source-Eurekalert