Reprogrammed energy metabolism, especially the Warburg effect (aerobic glycolysis), is an emerging hallmark of cancer. Different from other breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits high metabolic remodeling, increased aggressiveness and lack of targeted therapies. MicroRNAs (miRNA) are essential to TNBC malignant phenotypes. However, little is known about the contribution of miRNA to aerobic glycolysis in TNBC. Through an integrated analysis and functional verification, we reported that several miRNAs significantly correlates to the Warburg effect in TNBC, including miR-210-3p, miR-105-5p, and miR-767-5p. Ectopic expression of miR-210-3p enhanced glucose uptake, lactate production, extracellular acidification rate, colony formation ability, and reduced serum starvation-induced cell apoptosis. Moreover, GPD1L and CYGB were identified as two functional mediators of miR-210-3p in TNBC. Mechanistically, miR-210-3p targeted GPD1L to maintain HIF-1α stabilization and suppressed p53 activity via CYGB. Ultimately, miR-210-3p facilitated aerobic glycolysis through modulating the downstream glycolytic genes of HIF-1α and p53. Taken together, our results decipher miRNAs that regulate aerobic glycolysis and uncover that miR-210-3p specifically contributes to the Warburg effect in TNBC.

Background: Hypoxia is an important environmental factor and has been correlated with tumor progression, treatment resistance and poor prognosis in many solid tumors, including triple-negative breast cancer (TNBC). Emerging evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in tumor biology. However, little is known about the link between hypoxia and lncRNAs in TNBC.Methods: TNBC molecular profiles from The Cancer Genome Atlas (TCGA) were leveraged to identify hypoxia-related molecular alterations. Loss-of-function studies were performed to determine the regulatory role of MIR210HG in tumor glycolysis. The potential functions and mechanisms of hypoxia-MIR210HG axis were explored using qPCR, Western blotting, luciferase reporter assay, and polysome profiling.Results: We found that MIR210HG is a hypoxia-induced lncRNA in TNBC. Loss-of-function studies revealed that MIR210HG promoted the Warburg effect as demonstrated by glucose uptake, lactate production and expression of glycolytic components. Mechanistically, MIR210HG potentiated the metabolic transcription factor hypoxia-inducible factor 1α (HIF-1α) translation via directly binding to the 5’-UTR of HIF-1α mRNA, leading to increased HIF-1a protein level, thereby upregulating expression of glycolytic enzymes. MIR210HG knockdown in TNBC cells reduced their glycolytic metabolism and abolished their tumorigenic potential, indicating the glycolysis-dependent oncogenic activity of MIR210HG in TNBC. Moreover, MIR210HG was highly expressed in breast cancer and predicted poor clinical outcome.Conclusion: Our results decipher a positive feedback loop between hypoxia and MIR210HG that drive the Warburg effect and suggest that MIR210HG may be a good prognostic marker and therapeutic target for TNBC patients.

Breast cancer (BC) is the most frequently diagnosed malignant tumor among women in the world. BC is the heterogeneous tumor with different subtypes including luminal A-like, luminal B-like (HER2-/HER2+), HER2 enriched, and triple-negative BC. The therapeutic strategies including surgery, chemotherapy, radiotherapy, targeted therapy, and endocrine therapy are well developed and commonly used in the treatment of BC. However, some adverse effects of these conventional treatments limited their wide application in clinical. Therefore, it is necessary to develop more safe and more efficient individualized treatment strategies of the BC. Nanomedicine, as the most promising strategy for controlled and targeted drug delivery, is widely used in multiple aspects of cancer therapy. Importantly, accumulative evidences show that nanomedicine has achieved good outcomes in the treatment of BC and a huge amount of BC patients benefited from the nanomedicine related treatments. In this review, we summarized and discussed the major problems occurred during the administration of conventional treatment strategies for BC and the potential roles of nanomedicine in promoting the treatment efficacy of BC by overcoming obstacles of current treatment of BC.

Erastin is a small molecular compound that induces ferroptosis by binding to voltage‑dependent anion‑selective channel protein (VDAC)2, VDAC3 and solute carrier family 7 member 5 inhibiting the cystine/glutamate antiporter. However, to the best of our knowledge, the mechanism of erastin‑induced breast cancer cell death remains unclear. In present study aimed to explore the underlying mechanisms of the antitumor effects of erastin on breast cancer cells. Cellular viability was assessed using an MTT assay, a lactate dehydrogenase cytotoxicity assay kit was used to determine the cell death rate, the intracellular Fe²⁺ levels were determined using an iron colorimetric assay kit and western blotting was used to estimate the changes of autophagy‑associated proteins levels. The present study demonstrated that erastin inhibited the viability of breast cancer cells and induced breast cancer cell death in a dose‑dependent manner. Additionally, autophagy was activated by erastin, as demonstrated by upregulated expression levels of autophagy‑associated proteins in breast cancer cells. Bafilomycin A1, 3‑methyladenine and knockdown of autophagy related (ATG)5 with small interfering RNA prevented erastin‑induced breast cancer cell death and inhibited the erastin‑induced changes in the expression levels of the autophagy‑associated proteins beclin1, ATG5, ATG12, microtubule‑associated proteins 1A/1B light chain 3B (LC3B) and P62. Furthermore, erastin‑induced breast cancer cell death was inhibited by an iron chelator, deferoxamine, which inhibited the increases of erastin‑induced iron levels and inhibited the erastin‑induced changes in the expression levels of the autophagy‑related proteins beclin1, ATG5, ATG12, LC3B and P62. In summary, erastin triggered autophagic death in breast cancer cells by increasing intracellular iron levels.

Despite advancements in radiotherapy, chemotherapy, endocrine therapy, targeted therapy, and immunotherapy, resistance to therapy remains a pervasive challenge in oncology, in part owing to tumor heterogeneity. Identifying new therapeutic targets is key to addressing this challenge because it can both diversify and enhance existing treatment options, particularly through combination regimens. The cAMP response element-binding protein (CREB) is a transcription factor involved in various biological processes. It is aberrantly activated in several aggressive cancer types, including breast cancer. Clinically, high CREB expression is associated with increased breast tumor aggressiveness and poor prognosis. Functionally, CREB promotes breast cancer cell proliferation, survival, invasion, metastasis, as well as therapy resistance by deregulating genes related to apoptosis, cell cycle, and metabolism. Targeting CREB with small molecule inhibitors has demonstrated promise in preclinical studies. This review summarizes the current understanding of CREB mechanisms and their potential as a therapeutic target. SIGNIFICANCE STATEMENT: cAMP response element-binding protein (CREB) is a master regulator of multiple biological processes, including neurodevelopment, metabolic regulation, and immune response. CREB is a putative proto-oncogene in breast cancer that regulates the cell cycle, apoptosis, and cellular migration. Preclinical development of CREB-targeting small molecules is underway.