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

Chien-Hsiu Li; Chih-Yeu Fang; Ming-Hsien Chan; Pei-Jung Lu; Luo-Ping Ger; Jan-Show Chu; Yu-Chan Chang; Chi-Long Chen; Michael Hsiao

doi:10.1002/cjp2.313

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

J Pathol Clin Res. 2023 May;9(3):165-181. doi: 10.1002/cjp2.313. Epub 2023 Feb 13.

Authors

Chien-Hsiu Li^#¹, Chih-Yeu Fang^#², Ming-Hsien Chan¹, Pei-Jung Lu^{3

4}, Luo-Ping Ger^{5

6}, Jan-Show Chu^{7

8}, Yu-Chan Chang⁹, Chi-Long Chen^{7

8}, Michael Hsiao^{1

10}

Affiliations

¹ Genomics Research Center, Academia Sinica, Taipei, Taiwan.
² National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.
³ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
⁵ Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁶ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁷ Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁸ Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan.
⁹ Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁰ Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.

^# Contributed equally.

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.

Keywords: EP300; F11R; breast cancer; survival curve; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Adhesion Molecules* / genetics
E1A-Associated p300 Protein
Humans
Prognosis
RNA, Messenger
Receptors, Cell Surface / genetics
Triple Negative Breast Neoplasms* / genetics

Substances

Cell Adhesion Molecules
Receptors, Cell Surface
RNA, Messenger
F11R protein, human
EP300 protein, human
E1A-Associated p300 Protein