Ann Surg Treat Res.  2022 Aug;103(2):63-71. 10.4174/astr.2022.103.2.63.

Overexpression of FRAT1 protein is closely related to triple-negative breast cancer

• Nam SE
• Ko YS
• Park KS
• Jin T
• Yoo YB
• Yang JH
• Kim WY
• Han HS
• Lim SD
• Lee SE
• Kim WS

• KMID: 2532360
• DOI: http://doi.org/10.4174/astr.2022.103.2.63

Abstract

Purpose
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis and a lack of targeted therapy. Overexpression of FRAT1 is thought to be associated with this aggressive subtype of cancer. Here, we performed a comprehensive analysis and assessed the association between overexpression of FRAT1 and TNBC.
Methods
First, using different web-based bioinformatics platforms (TIMER 2.0, UALCAN, and GEPIA 2), the expression of FRAT1 was assessed. Then, the expression of the FRAT1 protein and hormone receptors and HER2 status were assessed by immunohistochemical analysis. For samples of tumors with equivocal immunoreactivity, we performed silver in situ hybridization of the HER2 gene to determine an accurate HER2 status. Next, we used the R package and bc-GenExMiner 4.8 to analyze the relationship between FRAT1 expression and clinicopathological parameters in breast cancer patients. Finally, we determined the relationship between FRAT1 overexpression and prognosis in patients.
Results
The expression of FRAT1 in breast cancer tissues is significantly higher than in normal tissue. FRAT1 expression was significantly related to worse overall survival (P < 0.05) and was correlated with these clinicopathological features: T stage, N stage, age, high histologic grade, estrogen receptor status, progesterone receptor status, Her-2 status, TNBC status, basal-like status, CK5/6 status, and Ki67 status.
Conclusion
FRAT1 was overexpressed in breast cancer compared to normal tissue, and it may be involved in the progression of breast cancer malignancy. This study provides suggestive evidence of the prognostic role of FRAT1 in breast cancer and the therapeutic target for TNBC.

Keyword

FRAT1; Prognosis; Triple negative breast neoplasms

Figure

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  Fig. 1 The expression of FRAT1 messenger RNA in Pan-cancer. Human FRAT1 expression levels in different tumor types from TCGA database were determined by TIMER 2.0 (http://timer.cistrome.org). TCGA, The Cancer Genome Atlas; TIMER, Tumor Immune Estimation Resource. ***P < 0.001, **P < 0.01, *P < 0.05.

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  Fig. 2 The expression of FRAT1 messenger RNA in breast cancer. (A) Expression of FRAT1 in breast cancer based on sample types by UALCAN (http://ualcan.path.uab.edu/index.html), P < 0.001. (B) The Expression of FRAT1 in breast cancer tissue and normal tissue generated by GEPIA 2 web (http://gepia2.cancer-pku.cn/#index); TCGA database, P < 0.01. GEPIA, Gene Expression Profiling Interactive Analysis; TCGA,The Cancer Genome Atlas.

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  Fig. 3 Immunohistochemical analysis of FRAT1 expression. (A) Negative reactivity of FRAT1 in the normal ductal and myoepithelial cells (×200). (B) Cytoplasmic and membranous expression of FRAT1 in breast cancer (×400).

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  Fig. 4 Kaplan-Meier survival analysis. Kaplan-Meier survival analysis demonstrated that the group with FRAT1 expression showed significantly worse overall survival than the one without FRAT1 expression.

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  Fig. 5 Relationship between FRAT1 expression and clinicopathological parameters in breast cancer patients. The box plot was retrieved from the Breast Cancer Gene-Expression Miner ver. 4.8 (http://bcgenex.ico.unicancer.fr/BC-GEM/GEM-Accueil.php?js=1). Global significant difference between groups was assessed by Welch t-test to generate P-values, along with the Dunnett-Tukey-Kramer test. ER, estrogen receptor; PR, progesterone receptor; HER2, HER2 receptor; TNBC, triple-negative breast cancer; IHC, immunohistochemistry; mRNA, messenger RNA.

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  Fig. 6 Relationship between FRAT1 messenger RNA expression and clinical outcomes in breast cancer patients in PrognoScan database (http://dna00.bio.kyutech.ac.jp/PrognoScan/index.html). Breast cancer; GSE9893; overall survival; hazard ratio, 1.33 (1.10–1.61), P = 0.010.

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  Fig. 7 Relationship between FRAT1 messenger RNA expression and clinical outcomes in breast cancer patients in R2: Kaplan-Meier scanner. Tumor breast invasive carcinoma; The Cancer Genome Atlas (TCGA); overall survival, P = 0.025.

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