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Emerging Role of Aberrant Glycosylation in Triple-Negative Breast Cancers (TnBCs)
Triple-negative breast cancers (TnBCs) represent a particularly aggressive subtype of breast cancer, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This subtype poses significant challenges in treatment due to its lack of targeted therapies, leading to poorer prognosis compared to other breast cancer types. Recent research has begun to unravel the complex role of glycosylation in cancer biology, particularly in TnBCs, where aberrant glycosylation patterns have been observed to play a pivotal role in cancer progression, metastasis, and resistance to therapy.
Glycosylation, the process of adding carbohydrate structures to proteins or lipids, is crucial for numerous biological functions including cell adhesion, signaling, and immune response. In TnBCs, alterations in glycosylation pathways lead to the expression of truncated or aberrant glycans, which can significantly influence tumor behavior. One of the most studied aberrant glycosylations in TnBCs is the Tn antigen, which is a truncated O-glycan structure. The presence of Tn antigen on the surface of cancer cells has been linked to increased invasiveness and metastatic potential. Studies have shown that Tn antigen expression correlates with poor prognosis in TnBC patients, suggesting its potential as a prognostic marker.
The implications of these glycosylation changes are multifaceted. Firstly, aberrant glycosylation can alter the interaction between cancer cells and their microenvironment. For instance, changes in sialylation, another form of glycosylation, can mask cancer cells from immune surveillance, thereby promoting immune evasion. This is particularly critical in TnBCs, where the immune system's role in controlling tumor growth is vital due to the lack of other therapeutic targets. Research has indicated that sialylated glycans on TnBC cells can inhibit natural killer (NK) cell activity, thus facilitating tumor progression.
Moreover, glycosylation changes can directly affect the efficacy of chemotherapy. For example, the overexpression of certain glycosyltransferases in TnBCs can lead to the modification of drug targets or transporters, potentially reducing the effectiveness of chemotherapeutic agents. This has been observed with drugs like doxorubicin, where altered glycosylation patterns on the cell surface can decrease drug uptake, contributing to chemoresistance, a common challenge in treating TnBCs.
From a diagnostic and therapeutic perspective, the unique glycosylation patterns in TnBCs offer potential avenues for targeted therapies. Glycan-targeted therapies, such as monoclonal antibodies against specific glycan structures, are being explored. For instance, antibodies targeting Tn antigens have shown promise in preclinical models by enhancing immune recognition and potentially reducing tumor growth. Additionally, inhibitors of glycosylation enzymes could be used to revert the cancer cells' glycosylation profile to a less aggressive state, thereby making them more susceptible to existing treatments.
Furthermore, the study of glycosylation in TnBCs has implications for personalized medicine. By profiling the glycosylation status of tumors, clinicians could tailor treatments more effectively. This approach could not only improve therapeutic outcomes but also minimize the side effects associated with broad-spectrum chemotherapy. The integration of glycomics with genomics and proteomics in TnBC research could lead to a more comprehensive understanding of the disease, paving the way for novel therapeutic strategies.
In conclusion, the emerging role of aberrant glycosylation in TnBCs underscores its significance in cancer biology. Understanding these changes not only provides insights into the mechanisms of cancer progression but also opens up new therapeutic windows. As research progresses, the potential of targeting glycosylation pathways could revolutionize the management of TnBCs, offering hope for better outcomes in this challenging cancer subtype.
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Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (Lehmann et al., 2011). TNBC accounts for about 15% of all breast cancer cases and is associated with poor prognosis and limited treatment options compared to other breast cancer subtypes. Aberrant glycosylation, a post-translational modification of proteins, has been shown to play a crucial role in the development and progression of various cancers, including TNBC.
Aberrant glycosylation in cancer cells can lead to the altered expression of glycan structures on cell surface receptors and adhesion molecules, thereby affecting cell signaling, cell-cell interactions, and immune response evasion (Dennis et al., 1999). Changes in glycosylation patterns of proteins can result in the aberrant activation of oncogenic signaling pathways, such as the PI3K/Akt and MAPK pathways, leading to increased cell proliferation, invasion, and metastasis in cancer cells (Granovsky et al., 2001). In TNBC, aberrant glycosylation has been shown to contribute to the aggressive phenotype of cancer cells and resistance to chemotherapy.
One of the key implications of aberrant glycosylation in TNBC is the modulation of immune responses in the tumor microenvironment. Alterations in glycosylation patterns of glycoproteins on cancer cells can lead to immune evasion by preventing recognition and attack by immune cells, such as T cells and natural killer (NK) cells (Adachi et al., 2005). Additionally, abnormal glycosylation of cell surface receptors, such as programmed death-ligand 1 (PD-L1), can inhibit the function of cytotoxic T lymphocytes (CTLs) and promote immune tolerance in the tumor microenvironment, leading to tumor progression and metastasis (Beckwith et al., 2017).
Furthermore, aberrant glycosylation of cell surface receptors, such as epidermal growth factor receptor (EGFR) and integrins, can enhance cell migration, invasion, and metastasis in TNBC through the dysregulation of cell adhesion and cytoskeletal rearrangement (Gupta et al., 2012). Changes in glycosylation patterns of integrins can result in the activation of focal adhesion kinase (FAK) and Rho GTPases, leading to increased cell motility and invasiveness in cancer cells (Pinho and Reis, 2015). Moreover, aberrant glycosylation of EGFR can promote ligand-independent receptor activation and downstream signaling cascades, contributing to tumor growth and metastasis in TNBC (Zakaria et al., 2019).
Targeting aberrant glycosylation in TNBC has emerged as a promising approach for the development of novel therapeutic strategies. Inhibitors of glycosylation enzymes, such as glycosyltransferases and glycosidases, have been investigated as potential anticancer agents to disrupt glycan biosynthesis and inhibit tumor progression in TNBC (Duarte et al., 2016). For example, inhibitors of N-acetylglucosaminyltransferase V (GnT-V), an enzyme involved in the biosynthesis of branched N-glycans, have been shown to suppress metastasis and increase sensitivity to chemotherapeutic agents in TNBC cell lines (Pinho et al., 2008).
Moreover, immunotherapies targeting abnormal glycosylation patterns on cancer cells have shown promising results in preclinical studies and clinical trials for the treatment of TNBC. Anti-glycan antibodies, such as anti-Tn and anti-sialyl-Tn antibodies, have been developed as potential diagnostic and therapeutic tools to target aberrant glycosylation on cancer cells and induce antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells (Beatson et al., 2015). In addition, glycoengineered antibodies targeting tumor-associated glycans, such as the Lewis antigen and T antigen, have been designed to enhance the immune response against cancer cells and improve patient outcomes in TNBC (Stowell et al., 2019).
In conclusion, aberrant glycosylation plays a critical role in the development and progression of TNBC by modulating immune responses, promoting cell migration and invasion, and conferring resistance to chemotherapy. Targeting abnormal glycosylation patterns on cancer cells represents a promising therapeutic approach for the treatment of TNBC and may lead to the development of novel immunotherapies and glycosylation inhibitors for improved patient outcomes.
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