Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review

Abstract

BackgroundTumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics.MethodsArticles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.ResultsIncreased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells.DiscussionFOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

The Characteristic of S100A7 Induction by the Hippo-YAP Pathway in Cervical and Glossopharyngeal Squamous Cell Carcinoma

“…Fourth, S100A7 is responsible for cell detachment induced-anoikis resistance and tumorigenicity in human oral cancer cells. [20,38] Thus, we speculate that YAP and S100A7 might act as the compensatory function depending on cell microenvironment in well differentiated cervical and glossopharyngeal SCC. When these cells are detached or cultured in high density, the Hippo pathway is activated and nuclear YAP is attenuated, which leads to S100A7 induction in order to perform the similar effects as YAP, such as maintenance of cell survival and/or suppression of cell differentiation.…”

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

“…While PPARc is upstream of many of the effectors that are influenced by BAR, the PPARc agonist rosiglitazone did not recapitulate the effects of BAR on gene expression or prevent loss of metabolic activity. Others have shown that FOXO3a is a target for triterpenoids in cancer [15,37].…”

“…A number of existing BC drugs target PI3K/AKT [15]. Although the mechanism for the anticancer activities of BAR are not fully understood, many signaling pathways, including mitochondrial regulation via the KEAP1/Nrf2 pathway and glycolytic regulation via the PI3K/mTOR pathway, have been implicated in the anticancer effects of BAR [16].…”

Metabolic advantages and vulnerabilities in brain metastases

“…In TNBC, metabolic dysregulation is driven by factors such as glutathione S-transferase Pi 1 (GSTP1), forkhead box O 3a (FOXO3a), and EGFR-induced c-Myc (43–45). Specifically, c-Myc represses thioredoxin-interacting protein (TXNIP), an inhibitor of glycolytic gene expression and glucose uptake (46).…”