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

Taylor S, Lam M, Pararasa C, Brown JE, Carmichael AR, Griffiths HR - Cancer Cell Int. (2015)

Bottom Line: Increased 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.The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET UK.

ABSTRACT

Background: Tumour 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.

Methods: Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.

Results: Increased 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.

Discussion: FOXO3a 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.

No MeSH data available.


Related in: MedlinePlus

FOXO3a regulation by Akt. Growth factors/hormone stimulate PI3k phosphorylation of Akt, FOXO3a is phosphorylated by Akt, 14-3-3 also binds FOXO3a DNA binding sites, further preventing its activity in the nucleus. It is then tagged for degradation via ubiquitination and then degraded in a proteasome. Adapted from (Wilson, 2009 [49]).
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Fig1: FOXO3a regulation by Akt. Growth factors/hormone stimulate PI3k phosphorylation of Akt, FOXO3a is phosphorylated by Akt, 14-3-3 also binds FOXO3a DNA binding sites, further preventing its activity in the nucleus. It is then tagged for degradation via ubiquitination and then degraded in a proteasome. Adapted from (Wilson, 2009 [49]).

Mentions: Genomic analysis of TNBC has revealed frequent associations with mutations in class 1 PI3k which lies directly upstream of FOXO3a [14]. Mutations within the tumour suppressor PTEN, a negative regulator of Akt activation, can result in constitutively active Akt and inhibit FOXO3a, so promoting HIF1 expression, antioxidant gene expression and an increase membrane translocation of glucose transporters and rate-limiting enzymes such as phosphofructokinase-1 [15] (FigureĀ 1).Figure 1


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

Taylor S, Lam M, Pararasa C, Brown JE, Carmichael AR, Griffiths HR - Cancer Cell Int. (2015)

FOXO3a regulation by Akt. Growth factors/hormone stimulate PI3k phosphorylation of Akt, FOXO3a is phosphorylated by Akt, 14-3-3 also binds FOXO3a DNA binding sites, further preventing its activity in the nucleus. It is then tagged for degradation via ubiquitination and then degraded in a proteasome. Adapted from (Wilson, 2009 [49]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4325954&req=5

Fig1: FOXO3a regulation by Akt. Growth factors/hormone stimulate PI3k phosphorylation of Akt, FOXO3a is phosphorylated by Akt, 14-3-3 also binds FOXO3a DNA binding sites, further preventing its activity in the nucleus. It is then tagged for degradation via ubiquitination and then degraded in a proteasome. Adapted from (Wilson, 2009 [49]).
Mentions: Genomic analysis of TNBC has revealed frequent associations with mutations in class 1 PI3k which lies directly upstream of FOXO3a [14]. Mutations within the tumour suppressor PTEN, a negative regulator of Akt activation, can result in constitutively active Akt and inhibit FOXO3a, so promoting HIF1 expression, antioxidant gene expression and an increase membrane translocation of glucose transporters and rate-limiting enzymes such as phosphofructokinase-1 [15] (FigureĀ 1).Figure 1

Bottom Line: Increased 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.The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET UK.

ABSTRACT

Background: Tumour 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.

Methods: Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.

Results: Increased 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.

Discussion: FOXO3a 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.

No MeSH data available.


Related in: MedlinePlus