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The activation of EP300 by F11R leads to EMT and acts as a prognostic factor in triple-negative breast cancers

Chien-Hsiu Li¹, Chih-Yeu Fang², Ming-Hsien Chan¹

¹Genomics Research Center, Academia Sinica, Taipei, Taiwan.

The Journal of Pathology. Clinical Research

|February 14, 2023

Abstract:

Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the F11R (F11 receptor) in tumours were inversely correlated to the expression of JAM-2 and JAM-3. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (p = 0.024, hazard ratio = 1.44 [1.05-1.99]). A 50-gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. F11R mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)-enriched (p = 0.0035) and basal-like BCa tumours (p = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (p < 0.001; Taipei Medical University [TMU] cohort, p < 0.001; Kaohsiung Veterans General Hospital [KVGH] cohort) or disease-free survival (p < 0.001 [TMU cohort], p = 0.034 [KVGH cohort]) in patients with BCa. Comparison of F11R levels in different subtypes revealed the association of poor prognosis with high levels of F11R among luminal (p < 0.001 [TMU cohort], p = 0.027 [KVGH cohort]), HER2 positive (p = 0.018 [TMU cohort], p = 0.037 [KVGH cohort]), and triple-negative (p = 0.013 [TMU cohort], p = 0.037 [KVGH cohort]) BCa. F11R-based RNA microarray analysis and Ingenuity Pathway Analysis were successful in profiling the detailed gene ontology of triple-negative BCa cells regulated by F11R. The EP300 transcription factor was highly correlated with F11R in BCa (R = 0.51, p < 0.001). By analysing these F11R-affected molecules with the L1000CDs datasets, we were able to predict some repurposing drugs for potential application in F11R-positive BCa treatment.

Insights

High F11 receptor (F11R) levels correlate with poor prognosis in breast cancer (BCa). This finding, unique to BCa, was observed across multiple subtypes, suggesting F11R as a potential therapeutic target.

Area of Science:

Oncology
Molecular Biology
Genomics

Background:

Junctional adhesion molecule (JAM) family members influence cancer progression.
The Cancer Genome Atlas (TCGA) dataset was utilized to investigate JAM family members in various cancers.

Purpose of the Study:

To examine the relationship between JAM family members and different cancer types.
To specifically analyze the role of F11 receptor (F11R) in breast cancer (BCa) prognosis and subtypes.

Main Methods:

Retrospective analysis of TCGA dataset for mRNA expression of F11R, JAM-2, and JAM-3.
Subtyping of BCa using a 50-gene molecular signature (PAM50).
Immunohistochemistry (IHC) to evaluate F11R protein levels in BCa patient cohorts (TMU and KVGH).
Gene ontology analysis and correlation studies with EP300 and L1000CDS datasets.

Main Results:

F11R mRNA levels inversely correlated with JAM-2 and JAM-3 expression, a relationship unique to BCa and linked to poor prognosis.
F11R mRNA expression was significantly elevated in HER2-enriched and basal-like BCa subtypes.
High F11R protein levels were consistently associated with poor overall survival and disease-free survival across multiple BCa subtypes (luminal, HER2-positive, triple-negative).
F11R expression correlated with EP300 and identified potential drug repurposing candidates for F11R-positive BCa.

Conclusions:

F11R is a significant prognostic biomarker in breast cancer, associated with poor outcomes across various subtypes.
Elevated F11R expression, particularly in specific BCa subtypes, warrants further investigation for targeted therapeutic strategies.
F11R-mediated pathways and its correlation with EP300 offer insights into BCa progression and potential drug targets.

Read full analysis

Keywords:

EP300 F11R breast cancer survival curve transcriptomics

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