Unravelling the mystery of hypoxia-induced miRNAs in breast cancer: A molecular cross-talk driving tumour progression and therapy resistance.

Breast cancer (BC) is estimated to be around 2.3 million new cases and 670 000 deaths in 2020 resulting it into the most frequent cancer globally and ranks fifth among mortalities. Numerous studies have established the link between BC and microRNAs (miRNAs), which are endogenous non-protein-coding master regulators that modulate genetic expressions and influences many physiological and pathological cellular processes. In addition, hypoxia, which also consequently leads to cancer, is a pivotal driver of biological behaviour and malignant traits of cancer cells and eventually tumour cell survival. Hypoxia and hypoxia-inducible factors (HIFs) further regulates the miRNAs expression and promotes invasion and metastasis via increased invasive, migratory, and intravasation properties of the cancer cell, which initiates the metastatic process. In subsequent stages of metastasis, cancer cells navigate immune escape, vascular extravasation, metabolic reprogramming, and tumour-stromal crosstalk at the distant tissue site. Hypoxia dysregulates cancer metabolism post-transcriptionally through miRNAs, promoting glycolysis and fatty acid metabolism by inducing the expression of genes such as GLUT1, SCD, lipidome, and glycolytic enzyme biosynthesis. Hypoxia, on the other hand, also regulates immunogenic reprogramming by circumventing immunosurveillance, perpetuating cell survival and progression via hampering CD-47, PD-L1 markers and T-cell activation. Another process of cancer known as programmed cell death types I and II also involves a complex intricate protein mediated by HIF-1α. Hypoxia-mediated drug resistance influence drug therapeutic effect via altering transporter flux, drug targets, and inactivate of apoptotic pathways. In this review, we are focusing on understanding the clinical implications of hypoxia-driven miRNAs in BC diagnosis and prognosis. Therapeutic landscape for these molecules remains largely untapped, resulting into conducting more research in this field for harbouring potential translational discoveries in the diagnosis, prognosis and therapeutics for BC.