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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.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).This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance.

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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Role of microRNA in endocrine resistance. microRNAs (miRNAs) that regulate the growth, survival, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis of breast cancer cells are implicated in the loss of responsiveness to endocrine therapies. miRNAs that are upregulated in endocrine resistance (red) could potentially be targets of RNA interference therapies, while miRNAs that are downregulated in endocrine resistance (green) could be targets of a replacement therapy in endocrine-resistant breast tumors. (A) miRNAs involved in tamoxifen resistance. (B) miRNAs involved in aromatase inhibitor (AI) resistance. Bim, Bcl-2-like 11; EGFR, epidermal growth factor receptor; ER, estrogen receptor; E2, 17β-estradiol; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MTDH, metadherin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGFR1β, transforming growth factor beta receptor 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.
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Fig4: Role of microRNA in endocrine resistance. microRNAs (miRNAs) that regulate the growth, survival, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis of breast cancer cells are implicated in the loss of responsiveness to endocrine therapies. miRNAs that are upregulated in endocrine resistance (red) could potentially be targets of RNA interference therapies, while miRNAs that are downregulated in endocrine resistance (green) could be targets of a replacement therapy in endocrine-resistant breast tumors. (A) miRNAs involved in tamoxifen resistance. (B) miRNAs involved in aromatase inhibitor (AI) resistance. Bim, Bcl-2-like 11; EGFR, epidermal growth factor receptor; ER, estrogen receptor; E2, 17β-estradiol; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MTDH, metadherin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGFR1β, transforming growth factor beta receptor 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.

Mentions: The miRNAs associated with endocrine resistance have been explored, and this effort has primarily focused on the differential expression of miRNAs in tamoxifen-resistant cells. miRNAs that inhibit ERα, such as miR-221/222, are implicated in resistance to anti-ERα therapies. One study showed that ectopic expression of miR-221 or miR-222 was enough to decrease ERα protein expression in MCF-7 and T47D breast cancer cells, and this led to the cells acquiring resistance to tamoxifen (Figure 4A) [79]. In addition, silencing of miR-221 and miR-222 in ERα-negative, endocrine-resistant MDA-MB-468 breast cancer cells has been shown to increase ERα expression and sensitize cells to tamoxifen-induced apoptosis [79].Figure 4


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)

Role of microRNA in endocrine resistance. microRNAs (miRNAs) that regulate the growth, survival, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis of breast cancer cells are implicated in the loss of responsiveness to endocrine therapies. miRNAs that are upregulated in endocrine resistance (red) could potentially be targets of RNA interference therapies, while miRNAs that are downregulated in endocrine resistance (green) could be targets of a replacement therapy in endocrine-resistant breast tumors. (A) miRNAs involved in tamoxifen resistance. (B) miRNAs involved in aromatase inhibitor (AI) resistance. Bim, Bcl-2-like 11; EGFR, epidermal growth factor receptor; ER, estrogen receptor; E2, 17β-estradiol; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MTDH, metadherin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGFR1β, transforming growth factor beta receptor 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Role of microRNA in endocrine resistance. microRNAs (miRNAs) that regulate the growth, survival, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis of breast cancer cells are implicated in the loss of responsiveness to endocrine therapies. miRNAs that are upregulated in endocrine resistance (red) could potentially be targets of RNA interference therapies, while miRNAs that are downregulated in endocrine resistance (green) could be targets of a replacement therapy in endocrine-resistant breast tumors. (A) miRNAs involved in tamoxifen resistance. (B) miRNAs involved in aromatase inhibitor (AI) resistance. Bim, Bcl-2-like 11; EGFR, epidermal growth factor receptor; ER, estrogen receptor; E2, 17β-estradiol; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MTDH, metadherin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGFR1β, transforming growth factor beta receptor 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.
Mentions: The miRNAs associated with endocrine resistance have been explored, and this effort has primarily focused on the differential expression of miRNAs in tamoxifen-resistant cells. miRNAs that inhibit ERα, such as miR-221/222, are implicated in resistance to anti-ERα therapies. One study showed that ectopic expression of miR-221 or miR-222 was enough to decrease ERα protein expression in MCF-7 and T47D breast cancer cells, and this led to the cells acquiring resistance to tamoxifen (Figure 4A) [79]. In addition, silencing of miR-221 and miR-222 in ERα-negative, endocrine-resistant MDA-MB-468 breast cancer cells has been shown to increase ERα expression and sensitize cells to tamoxifen-induced apoptosis [79].Figure 4

Bottom Line: 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).This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance.

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