Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens

Abstract

Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological and clinical observations the TNBC related mortality is very high worldwide. Emerging studies have clearly demonstrated that hypoxia regulates the critical metabolic, developmental, and survival pathways in TNBC, which include glycolysis and angiogenesis. Alterations to these pathways accelerate the cancer stem cells (CSCs) enrichment and immune escape, which further lead to tumor invasion, migration, and metastasis. Beside this, hypoxia also manipulates the epigenetic plasticity and DNA damage response (DDR) to syndicate TNBC survival and its progression. Hypoxia fundamentally creates the low oxygen condition responsible for the alteration in Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within the tumor microenvironment, allowing tumors to survive and making them resistant to various therapies. Therefore, there is an urgent need for society to establish target-based therapies that overcome the resistance and limitations of the current treatment plan for TNBC. In this review article, we have thoroughly discussed the plausible significance of HIF-1α as a target in various therapeutic regimens such as chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic therapy, adoptive cell therapy, combination therapies, antibody drug conjugates and cancer vaccines. Further, we also reviewed here the intrinsic mechanism and existing issues in targeting HIF-1α while improvising the current therapeutic strategies. This review highlights and discusses the future perspectives and the major alternatives to overcome TNBC resistance by targeting hypoxia-induced signaling.

Design of Specific and Efficient sgRNA for CRISPR/Cas9 System to Knockout Superoxide Dismutase 2 in Breast Cancer Stem Cells

“…Several studies have showed that BCSCs show higher levels of SOD2 compared to the non-BCSC population. This high expression strongly correlates with their aggressiveness, including stemness and metastasis (Srivastava et al, 2023;Wanandi et al, 2019). However, specific sequence variation in human SOD2 contributing to the aggressive properties remains unknown.…”

Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

“…For instance, hypoxia commonly happens in rapidly growing tumors that outsource the available blood supply, resulting in hypoxia within the TME. Hypoxia induces expresses the Angiogenic Growth Factors, which are associated with the stabilization and activation of hypoxia-inducible factors (HIFs) which are transcription factors that regulate the expression of genes involved in various aspects of tumor progression, including immunosuppression [19]. It can also promote the recruitment and expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), both of which contribute to the immunosuppression [20].…”

Integrated Proteogenomic Analysis Reveals Distinct Potentially Actionable Therapeutic Vulnerabilities in Triple-Negative Breast Cancer Subtypes

“…Although these genomic studies have led to the rationale for ongoing clinical trials involving androgen receptor and PARP inhibitors in biomarker-selected populations, very few options currently exist for targeted therapy in TNBC. Moreover, several studies have demonstrated that hypoxia also induces genomic alterations in TNBC patients and is responsible for treatment resistance and recurrence [8][9][10][11]. Thus, there is a need for an improved understanding of actionable molecular alterations and their correlation with functional changes predicting drug response.…”