Breast cancer (BC) is the most common cancer in women in the United States. Approximately 1/3 of BCs are ER-negative (ERneg) and among these approximately 30,000 diagnoses of triple negative (TN: ER-negative, PR-negative, Her2-negative) BCs are made per year in the U.S. Although ~50% of ER-positive (ERpos) BCs can be prevented by anti-estrogenic agents belonging to two classes: selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), no drugs have been shown to prevent ERneg cancers, including TN BCs. The need for such agents is evident in the more aggressive behavior of TN BCs, which grow faster, spread earlier and recur more often than other subtypes. Furthermore, the incidence of TN BCs is higher in young African American and Hispanic/Latina women and in women with BRCA1 mutations. Development of agents targeting non-ER-based oncogenic pathways offers a potential alternative approach for prevention of ERneg/TN BCs. The drug HJC0152 targets glucose metabolism and associated energy production. The relevance of this mechanism to carcinogenesis was first described by Otto Warburg in the 1920s. The ?Warburg effect? refers to the dysregulated energy metabolism in cancer cells, including BC cells, which exhibit increased glycolysis, with rates up to 200 times higher than in comparable normal cells. Etiologically this increased glycolysis may be related to abnormalities of glucose transport or breakdown, aberrant glycolytic enzymes, or malfunction of the mitochondrial respiratory chain. In particular, BC stem cells depend on aberrant glycolysis and are sensitive to inhibition of glucose metabolism. In contrast to normal cells which further catalyze the product of glycolysis, pyruvate, into carbon dioxide and water via the Krebs cycle (tricarboxylic acid/TCA cycle) and mitochondrial oxidative phosphorylation (OXPHOS) to efficiently produce ATPs, aberrant glucose metabolism in cancer cells, involving upregulated glycolysis, results in increased cell growth and malignant transformation. Although such metabolic remodeling is being studied in various cancer cell types, the role played by aberrant glucose metabolism and the mitochondrial respiratory chain in ERneg/TN BC carcinogenesis, particularly for the purpose of cancer prevention, has not been adequately explored. Various anti-cancer therapies that target glycolysis and energy metabolism are being studied, but potency, specificity and toxicity have posed challenges to drug development. None is approved for cancer prevention. A newly developed group of glucose/energy metabolism modulators show promise for prevention. Among these, HJC0152 gains support as a preventive agent for ERneg and TN BC from ERneg BC mouse model studies. In MMTV-erbB2 transgenic mice studies, HJC0152 blocked mammary tumor development by 84-100% and reduced and reversed premalignant lesions. This agent also inhibited glycolysis, differentially regulated glycolytic enzyme expression and the function of mitochondrial respiratory complexes in ERpos and TN BC cells. A number of glycolytic enzymes are significantly induced after HJC0152 treatment. HJC0152 also inhibits mitochondrial complexes IV and V (ATP synthase). Other mechanistic actions of HJC0152 also potentially contribute to its anti-cancer activity. As a derivative of niclosamide, an FDA-approved anti-tapeworm drug which inhibits activation of the pro-proliferative signal transducers and activators of transcription (STATs) pathway, HJC0152 likely also acts through this additional mechanism. Another target of niclosamide is the Wnt signaling pathway, also known to play a key role in carcinogenesis. As with its parent molecule, HC0152 potentially exerts anti-cancer effects via inhibition of the Wnt pathway. Additional mechanisms of niclosamide action, meriting examination following HC0152 intervention, include inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) and mammalian target of rapamycin complex 1 (mTORC1) pathways. Long-term administration of this agent shows that it has low toxicity, supporting its investigation for prevention of ERneg/TN mammary cancer.
