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Tamoxifen resistance in breast cancer.

Chang M - Biomol Ther (Seoul) (2012)

Bottom Line: Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER.It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer.Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Pharmaceutical Science, College of Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

ABSTRACT
Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER. It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. This review summarizes the roles of ER as the therapeutic target of tamoxifen in cancer treatment, clinical values and issues of tamoxifen use, and molecular mechanisms of tamoxifen resistance. Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

No MeSH data available.


Related in: MedlinePlus

A scheme showing the different mechanisms of tamoxifen resistance: (1) Loss of ERα expression and function lead to disappearance of the molecular target for tamoxifen (2) altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, (3) ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, (4) altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes such as CYP2D6, (5) regulation of autophagy and/or apoptosis,(6) ER-negative cancer stem cells that differentiate over growth inhibition of ER-positive cancer cells upon antiestrogen treatment, and(7) antioxidant protein-mediated cell survival in which tamoxifen prevents repression of antioxidant proteins, such as Prx5 leading to cell survival and resistance to tamoxifen treatment.
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Figure 003: A scheme showing the different mechanisms of tamoxifen resistance: (1) Loss of ERα expression and function lead to disappearance of the molecular target for tamoxifen (2) altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, (3) ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, (4) altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes such as CYP2D6, (5) regulation of autophagy and/or apoptosis,(6) ER-negative cancer stem cells that differentiate over growth inhibition of ER-positive cancer cells upon antiestrogen treatment, and(7) antioxidant protein-mediated cell survival in which tamoxifen prevents repression of antioxidant proteins, such as Prx5 leading to cell survival and resistance to tamoxifen treatment.

Mentions: interaction and their activities on the Prx5 gene expression leads to decreased apoptosis in an ER ligand-dependent manner (Fig. 3 ).


Tamoxifen resistance in breast cancer.

Chang M - Biomol Ther (Seoul) (2012)

A scheme showing the different mechanisms of tamoxifen resistance: (1) Loss of ERα expression and function lead to disappearance of the molecular target for tamoxifen (2) altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, (3) ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, (4) altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes such as CYP2D6, (5) regulation of autophagy and/or apoptosis,(6) ER-negative cancer stem cells that differentiate over growth inhibition of ER-positive cancer cells upon antiestrogen treatment, and(7) antioxidant protein-mediated cell survival in which tamoxifen prevents repression of antioxidant proteins, such as Prx5 leading to cell survival and resistance to tamoxifen treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3794521&req=5

Figure 003: A scheme showing the different mechanisms of tamoxifen resistance: (1) Loss of ERα expression and function lead to disappearance of the molecular target for tamoxifen (2) altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, (3) ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, (4) altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes such as CYP2D6, (5) regulation of autophagy and/or apoptosis,(6) ER-negative cancer stem cells that differentiate over growth inhibition of ER-positive cancer cells upon antiestrogen treatment, and(7) antioxidant protein-mediated cell survival in which tamoxifen prevents repression of antioxidant proteins, such as Prx5 leading to cell survival and resistance to tamoxifen treatment.
Mentions: interaction and their activities on the Prx5 gene expression leads to decreased apoptosis in an ER ligand-dependent manner (Fig. 3 ).

Bottom Line: Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER.It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer.Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Pharmaceutical Science, College of Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

ABSTRACT
Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER. It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. This review summarizes the roles of ER as the therapeutic target of tamoxifen in cancer treatment, clinical values and issues of tamoxifen use, and molecular mechanisms of tamoxifen resistance. Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

No MeSH data available.


Related in: MedlinePlus