Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer

Perić, Luka; Vukadin, Sonja; Petrovic, Ana; Kuna, Lucija; Pušeljić, Nora; Sikora, Renata; Rožac, Karla; Vcev, Aleksandar; Smolić, Martina

doi:10.3390/biomedicines10123265

Cited by 9 publications

(7 citation statements)

References 118 publications

(159 reference statements)

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“…A relatively lower abundance of multi-antennary N-glycans was found as a characteristic of the luminal subtypes. The finding concerning the enhanced level of high-mannose glycans in breast cancer tissues, when compared with normal tissues associated with breast cancer diagnosis was reported 65 and can be connected with potential glycan-based targeted therapy or immunotherapy 66 in the future. The elevation of high-mannose N-glycans was also correlated with vascular invasion and lymph node involvement 35 .…”

Section: Discussionmentioning

confidence: 87%

“…While this comprehensive glycomic profiling technique has good clinical potential, further studies focusing on isomerism of sialic moieties could be crucial for understanding oncological consequences for different breast cancer cellular types. Recent research has shown that targeting N-glycan processing pathways may be a promising therapeutic approach for breast cancer 66 – 68 . In particular, inhibition of the enzyme N-acetylglucosaminyltransferase V (GnT-V) involved in the synthesis of certain N-glycans, has been shown to inhibit LVI and metastasis in breast cancer models 69 .…”

Section: Discussionmentioning

confidence: 99%

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N-glycan profiling of tissue samples to aid breast cancer subtyping

Benesova,

Nenutil,

Urminsky

et al. 2024

Sci Rep

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Breast cancer is a highly heterogeneous disease. Its intrinsic subtype classification for diagnosis and choice of therapy traditionally relies on the presence of characteristic receptors. Unfortunately, this classification is often not sufficient for precise prediction of disease prognosis and treatment efficacy. The N-glycan profiles of 145 tumors and 10 healthy breast tissues were determined using Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry. The tumor samples were classified into Mucinous, Lobular, No-Special-Type, Human Epidermal Growth Factor 2 + , and Triple-Negative Breast Cancer subtypes. Statistical analysis was conducted using the reproducibility-optimized test statistic software package in R, and the Wilcoxon rank sum test with continuity correction. In total, 92 N-glycans were detected and quantified, with 59 consistently observed in over half of the samples. Significant variations in N-glycan signals were found among subtypes. Mucinous tumor samples exhibited the most distinct changes, with 28 significantly altered N-glycan signals. Increased levels of tri- and tetra-antennary N-glycans were notably present in this subtype. Triple-Negative Breast Cancer showed more N-glycans with additional mannose units, a factor associated with cancer progression. Individual N-glycans differentiated Human Epidermal Growth Factor 2 + , No-Special-Type, and Lobular cancers, whereas lower fucosylation and branching levels were found in N-glycans significantly increased in Luminal subtypes (Lobular and No-Special-Type tumors). Clinically normal breast tissues featured a higher abundance of signals corresponding to N-glycans with bisecting moiety. This research confirms that histologically distinct breast cancer subtypes have a quantitatively unique set of N-glycans linked to clinical parameters like tumor size, proliferative rate, lymphovascular invasion, and metastases to lymph nodes. The presented results provide novel information that N-glycan profiling could accurately classify human breast cancer samples, offer stratification of patients, and ongoing disease monitoring.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

N-glycan profiling of tissue samples to aid breast cancer subtyping

Benesova,

Nenutil,

Urminsky

et al. 2024

Sci Rep

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“…These inhibitors could induce receptor degradation, thereby blocking cell proliferation. This speculation is particularly intriguing given the growing interest in enzymes involved in glycosylation pathways as novel therapeutic targets in BC [37].…”

Section: Discussionmentioning

confidence: 99%

PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells

Cipolletti

Acconcia

2023

Preprint

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Purpose: Metabolic reprogramming in breast cancer (BC) subtypes offers potential personalized treatment targets. Estrogen receptor α (ERα)-positive BC patients undergoing endocrine therapy (ET) can develop ET-resistant metastatic disease. Specific mutations, like Y537S in ERα, drive uncontrolled metastatic cell proliferation. Targeting mutant receptor levels shows promise for inhibiting growth in metastatic BC expressing ERα variants. Additionally, metabolic reprogramming occurs in ERα Y537S mutant cells. Consequently, we conducted a screen to identify metabolic proteins reducing intracellular levels of ERα Y537S and inhibiting cell proliferation. Methods: Nine metabolic proteins were identified in a siRNA-based screen, with phosphomannose mutase 2 (PMM2) showing the most promise. We measured the impact of PMM2 depletion on ERα stability and cell proliferation in ERα Y537S mutant cells. Additionally, we tested the effect of PMM2 reduction on the hyperactive phenotype of the mutant and its proliferation when combined with metastatic BC treatment drugs. Results: PMM2 emerged as a significant target due to its correlation with better relapse-free survival, overexpression in ERα-positive tumors, and its elevation in ERα Y537S-expressing cells. Depletion of PMM2 induces degradation of ERα Y537S, inhibits cell proliferation, and reduces ERα signaling. Notably, reducing PMM2 levels re-sensitizes ERα Y537S-expressing cells to certain ET drugs and CDK4/CDK6 inhibitors. Mechanistically, depletion of PMM2 leads to a reduction in ESR1 mRNA levels, resulting in decreased ERα receptor protein expression. Furthermore, reduction of PMM2 decreases FOXA1 levels, which plays a crucial role in ERα regulation. Conclusions: Our findings establish PMM2 as an innovative therapeutic target for metastatic BC expressing the ERα Y537S variant, offering alternative strategies for managing and treating this disease.

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“…Aberrant glycosylation, a general characteristic feature of tumor cells, can lead to changes in both N-glycan and O-glycan structures, resulting in abnormal carbohydrate structures referred to as tumor-associated carbohydrates (TACAs). The specific types of glycans present in TACAs can vary depending on the cancer type and the glycosylation alterations occurring within the tumor cells [60]. Common alterations in cancer glycosylation include defects in glycan maturation, causing the expression of truncated glycan chains, as well as the expression of complex glycan motifs and loss of certain glycans [61].…”

Section: The Glycosylation Signature Of Metastatic Checkpointsmentioning

confidence: 99%

Cancer Stem Cell Metastatic Checkpoints and Glycosylation Patterns: Implications for Therapeutic Strategies

Aghamiri,

Amin

2024

Kinases and Phosphatases

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Cancer stem cells (CSCs), found within tumors, are powerful drivers of disease recurrence and metastasis. Their abilities to self-renew and maintain stem-like properties make treatment difficult, as their heterogeneity and metastatic properties can lead to resistance and limit the effectiveness of standard therapies. Given their significance, CSCs are typically isolated based on combinations of markers, which often indicate heterogeneous populations of CSCs. The lack of consensus in cell characterization poses challenges in defining and targeting these cells for effective therapeutic interventions. In this review, we suggest five promising molecules—ABCB5, CD26, CD66c, uPAR, and Trop-2—chosen specifically for their distinct distribution within cancer types and clinical relevance. These markers, expressed at the cell surface of CSCs, could significantly enhance the specificity of cancer stemness characterization. This review focuses on describing their pivotal roles as biomarker checkpoints for metastasis. Additionally, this review outlines existing literature on glycosylation modifications, which present intriguing epitopes aimed at modulating the stability and function of these markers. Finally, we summarize several promising in vivo and clinical trial approaches targeting the mentioned surface markers, offering potential solutions to overcome the therapeutic resistance of CSCs and addressing current gaps in treatment strategies.

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Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer

Cited by 9 publications

References 118 publications

N-glycan profiling of tissue samples to aid breast cancer subtyping

N-glycan profiling of tissue samples to aid breast cancer subtyping

PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells

Cancer Stem Cell Metastatic Checkpoints and Glycosylation Patterns: Implications for Therapeutic Strategies

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