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Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA.

Hayes EL, Lewis-Wambi JS - Breast Cancer Res. (2015)

Bottom Line: However, resistance to these agents has become a major clinical obstacle.Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability.Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

View Article: PubMed Central - PubMed

ABSTRACT
Endocrine therapies such as tamoxifen and aromatase inhibitors are the standard treatment options for estrogen receptor-positive breast cancer patients. However, resistance to these agents has become a major clinical obstacle. Potential mechanisms of resistance to endocrine therapies have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of noncoding RNA (ncRNA). Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability. Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance. Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

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Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.
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Fig1: Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.

Mentions: Many of the key pathways involved in tamoxifen resistance involve growth factors, such as human epidermal growth factor receptor 2 (HER2) (Figure 1A). The growth of the tamoxifen-resistant cell model MCF-7/HER2-18 (HER2 overexpressing) is increased with treatment of tamoxifen, revealing a crosstalk between HER2 and ERα [20]. Likewise, early in vivo studies of breast tumors by Gottardis and Jordan revealed that, in the process of acquiring tamoxifen resistance, tumors may gain the ability to grow in a tamoxifen-stimulated manner [21]. There is strong evidence that the ability of tamoxifen to function as an agonist or an antagonist is dependent on whether it recruits coactivators or corepressors to the ERα transcription complex [22]. Perhaps the most studied coregulator of ERα is the amplified in breast cancer 1 (AIB1) protein. Increased expression of AIB1 correlates with tamoxifen resistance since AIB1 expression contributes to the agonistic activity of tamoxifen – especially in the presence of HER2 (Figure 1A) [23].Figure 1


Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA.

Hayes EL, Lewis-Wambi JS - Breast Cancer Res. (2015)

Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4362832&req=5

Fig1: Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.
Mentions: Many of the key pathways involved in tamoxifen resistance involve growth factors, such as human epidermal growth factor receptor 2 (HER2) (Figure 1A). The growth of the tamoxifen-resistant cell model MCF-7/HER2-18 (HER2 overexpressing) is increased with treatment of tamoxifen, revealing a crosstalk between HER2 and ERα [20]. Likewise, early in vivo studies of breast tumors by Gottardis and Jordan revealed that, in the process of acquiring tamoxifen resistance, tumors may gain the ability to grow in a tamoxifen-stimulated manner [21]. There is strong evidence that the ability of tamoxifen to function as an agonist or an antagonist is dependent on whether it recruits coactivators or corepressors to the ERα transcription complex [22]. Perhaps the most studied coregulator of ERα is the amplified in breast cancer 1 (AIB1) protein. Increased expression of AIB1 correlates with tamoxifen resistance since AIB1 expression contributes to the agonistic activity of tamoxifen – especially in the presence of HER2 (Figure 1A) [23].Figure 1

Bottom Line: However, resistance to these agents has become a major clinical obstacle.Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability.Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

View Article: PubMed Central - PubMed

ABSTRACT
Endocrine therapies such as tamoxifen and aromatase inhibitors are the standard treatment options for estrogen receptor-positive breast cancer patients. However, resistance to these agents has become a major clinical obstacle. Potential mechanisms of resistance to endocrine therapies have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of noncoding RNA (ncRNA). Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability. Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance. Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

Show MeSH
Related in: MedlinePlus