Abstract
The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway.
Highlights
Transforming growth factor-β (TGF-β) is a multi-functional secreted cytokine that plays pivotal roles in early development and adult tissue maintenance [1,2]
Such studies reveal the role played by HMG20A in the LSD1-CoREST complex, which is necessary for TGF-β-mediated epithelial to mesenchymal transition (EMT) via epigenetic control of SNAI1 expression
Related studies revealed that TGF-β-mediated signaling can lead to staphylococcal nuclease domain-containing 1 (SND1) transcriptional activation [71], thereby forming a positive feedback loop to amplify TGF-β signals, which could account for the tumor-promoting properties of TGF-β signaling in advanced stages of metastatic breast cancer (Figure 4, right)
Summary
Transforming growth factor-β (TGF-β) is a multi-functional secreted cytokine that plays pivotal roles in early development and adult tissue maintenance [1,2]. The SMADs relay the signal from the cell surface to the nucleus resulting in changes in expression of specific target genes. SMAD3 and SMAD4 (but not SMAD2) can bind directly to specific DNA motifs (50 -CAGA-30 elements) to regulate expression of target genes. Upon TβR1 activation, R-SMADs (Regulatory SMADs) become phosphorylated and form heteromeric complexes with SMAD4. Consistent with its function as a tumor-suppressor, in many cancers, genes encoding components of the TGF-β signaling pathway have been either deleted or mutated. A classic example of this is the finding that SMAD4 is frequently disrupted and inactivated in many types of cancer including 50% of pancreatic cancer patients [13] This is not the case for breast cancer since such specific mutations in TGF-β signaling components are relatively rare. Each nucleosome comprises short stretches of DNA, approximately 146 base pairs in length, wrapped around octamers of histone proteins (Figure 1)
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