Key protein identified as a marker in aggressive breast cancer

Breast Cancer News: Researchers from the University of Catania and Sapienza University of Rome have made a significant breakthrough in understanding triple-negative breast cancer (TNBC), a particularly aggressive form of breast cancer. This Breast Cancer News report delves into their discovery of a key protein that could potentially guide prognosis and treatment strategies for TNBC patients.


Key protein identified as a marker in aggressive breast cancer

What is Triple-Negative Breast Cancer?
Triple-negative breast cancer is a subtype of breast cancer that does not express estrogen receptors, progesterone receptors, or the HER2 protein. This lack of expression makes it difficult to treat with common hormonal therapies or drugs that target HER2. TNBC accounts for approximately 15-20% of all breast cancer cases and is known for its aggressive nature and poor prognosis. Patients with TNBC often have a lower overall survival rate and a higher likelihood of recurrence compared to other breast cancer subtypes.
 
The Role of Poliovirus Receptor-Like 3 Protein
In their study, researchers focused on 83 immune-related genes and their expression in TNBC. They found that the Poliovirus Receptor-Like 3 protein (PVRL3), also known as CD113 or Nectin3, is a significant negative prognostic marker in TNBC patients. Higher levels of PVRL3 are associated with lower overall survival rates. This protein, which belongs to a family of immunoglobulin-like cellular adhesion molecules, plays a crucial role in calcium-independent cellular adhesion and immune system regulation.
 
How PVRL3 Influences Cancer Progression
PVRL3 interacts with the TIGIT receptor on T cells and Natural Killer (NK) cells, playing a role in immune evasion by the tumor. This interaction suggests that PVRL3 helps the tumor to avoid being attacked by the body's immune system, thereby promoting tumor growth and spread. The interaction between PVRL3 and TIGIT emphasizes its influence in modulating immune responses, hinting at possible opportunities for new treatments.
 
Studies have shown that PVRL3 can influence tumor growth and metastasis by modulating intercellular connections and cell signaling. In various cancer types, such as ovarian carcinoma, nasopharyngeal carcinoma, prostate carcinoma, and lung adenocarcinoma, altered expression of PVRL3 has been observed to contribute to the invasive capacity of tumor cells. This facilitates their dissemination to other tissues, leading to a worse prognosis. Additionally, evidence suggests that PVRL3 may play a role in the tumor microenvironment, influencing the local immune response and interaction with stromal cells.
 
The Connection with EZH2
Further investigation revealed that PVRL3 expression is regulated by the Enhancer of Zeste Homolog 2 (EZH2) protein, an epigenetic regulator known for its role in gene silencing and cancer progression. EZH2 is often overexpressed in cancers and is associated with poor prognosis. The study found that inhibiting EZH2 could decrease PVRL3 levels, providing a potential pathway for targeted therapy in TNBC.
 
EZH2 is a component of the polycomb repressive complex 2 (PRC2) and is involved in catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification crucial for gene silencing. In cancer, EZH2 promotes tumor progression through various mechanisms, including enhancing the metabolic profile of tumors, promoting cell proliferation, and facilitating metastasis. The overexpression of EZH2 has been linked to treatment resistance, making it a key target for therapeutic intervention.
 
Experimental Methods and Findings
The researchers conducted their experiments using various TNBC cell lines, treating them with different inhibitors that target EZH2. They observed that inhibition of EZH2 led to a significant reduction in PVRL3 expression in the TNBC cell lines that were tested. This finding supports the idea that EZH2 inhibitors could be used to manage PVRL3 levels and potentially control the aggressiveness of TNBC.
 
The experiments involved treating MDA-MB-231 cells, a common TNBC cell line, with a range of compounds known to affect histone modifications. These included inhibitors like BIX01294, GSK343, JQ1, GSK2801, and Vorinostat. Among these, GSK343, an EZH2 inhibitor, significantly reduced PVRL3 expression levels by about 30%. This decrease in PVRL3 expression underscores the potential of targeting the EZH2-PVRL3 axis in therapeutic strategies.
 
Computational Analysis
To further understand the regulation of PVRL3, the researchers conducted computational analyses to identify transcription factors that could interact with the PVRL3 promoter region. They utilized databases like Enrichr and ARCHS4 RNA-seq to predict potential transcription factors and to identify genes co-expressed with PVRL3. This analysis confirmed EZH2 as a significant regulator of PVRL3, highlighting its role in modulating gene expression through epigenetic mechanisms.
 
Implications for Treatment
The identification of PVRL3 as a negative prognostic marker and its regulation by EZH2 opens new avenues for the treatment of TNBC. Targeting the EZH2-PVRL3 regulatory axis could provide a new therapeutic strategy, especially for patients whose tumors express high levels of both PVRL3 and EZH2. This personalized approach could improve treatment outcomes and offer new hope for patients with this aggressive cancer subtype.
 
Several EZH2 inhibitors are currently in clinical trials, and some have already been approved for other cancer types. For instance, Tazemetostat (EPZ-6438) is approved for treating epithelioid sarcoma and follicular lymphoma. Combining these inhibitors with other therapies targeting the PVRL3-TIGIT axis could enhance the efficacy of treatment, reducing tumor growth and improving survival rates in TNBC patients.
 
Study Limitations and Future Directions
While the study provides significant insights, it also has some limitations. The analyses were limited to mRNA data, and no protein-level validation was performed. Additionally, the study did not correct for multiple comparisons in survival analyses, which could affect the statistical power of the findings. Future research should include proteomic validation and explore larger, more comprehensive datasets to enhance the robustness and applicability of the results.
 
Conclusion
This discovery is a significant step forward in understanding the molecular mechanisms underlying TNBC and provides a potential new target for personalized therapy. By identifying and targeting key proteins involved in cancer progression, researchers hope to develop more effective treatments that can improve survival rates and quality of life for patients with this challenging disease.
 
The study findings were published in the peer-reviewed journal Cells.
https://www.mdpi.com/2073-4409/13/15/1299
 
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