Clinical Significance of Annexin A2 Expression in Breast Cancer Patients.

Lee D. Gibbs,Rajesh Nandy,Cheryl M. Lewis,Pankaj Chaudhary,Sayantan Maji,Jamboor K. Vishwanatha,Kelsey Mansheim

doi:10.3390/cancers13010002

Abstract

Simple SummaryAnnexin A2 (AnxA2) is a Ca++-dependent phospholipid-binding protein that is involved in invasion and metastasis of breast cancer. However, the expression of AnxA2 in breast cancer patients has not been reported. Here, we show that the expression of AnxA2 was high in tumor tissues and serum samples of breast cancer patients compared to non-cancer patients. The high expression of serum AnxA2 in breast cancer was associated with tumor grade and poor survival. The expression and diagnostic value of serum AnxA2 was high in triple-negative breast cancer (TNBC) subtypes and associated with the phosphorylation of AnxA2 at tyrosine 23. Overall, this study highlights the diagnostic and prognostic significance of AnxA2 in breast cancer.Increasing evidence suggests that AnxA2 contributes to invasion and metastasis of breast cancer. However, the clinical significance of AnxA2 expression in breast cancer has not been reported. The expression of AnxA2 in cell lines, tumor tissues, and serum samples of breast cancer patients were analyzed by immunoblotting, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. We found that AnxA2 was significantly upregulated in tumor tissues and serum samples of breast cancer patients compared with normal controls. The high expression of serum AnxA2 was significantly associated with tumor grades and poor survival of the breast cancer patients. Based on molecular subtypes, AnxA2 expression was significantly elevated in tumor tissues and serum samples of triple-negative breast cancer (TNBC) patients compared with other breast cancer subtypes. Our analyses on breast cancer cell lines demonstrated that secretion of AnxA2 is associated with its tyrosine 23 (Tyr23) phosphorylation in cells. The expression of non-phosphomimetic mutant of AnxA2 in HCC1395 cells inhibits its secretion from cells compared to wild-type AnxA2, which further suggest that Tyr23 phosphorylation is a critical step for AnxA2 secretion from TNBC cells. Our analysis of AnxA2 phosphorylation in clinical samples further confirmed that the phosphorylation of AnxA2 at Tyr23 was high in tumor tissues of TNBC patients compared to matched adjacent non-tumorigenic breast tissues. Furthermore, we observed that the diagnostic value of serum AnxA2 was significantly high in TNBC compared with other breast cancer subtypes. These findings suggest that serum AnxA2 concentration could be a potential diagnostic biomarker for TNBC patients.

Highlights

Breast cancer is the most common and second leading cause of cancer-related deaths among North American women, with the expectation that 276,480 new cases will be diagnosed with 42,170 deaths in 2020 [1]
Our results suggest that the secretion of Annexin A2 (AnxA2) is high in triple-negative breast cancer (TNBC) cell lines compared to non-tumorigenic, estrogen receptor (ER)+, progesterone receptor (PR)+, and/or human epidermal growth factor receptor type 2 (HER2)+ breast cancer cell lines (Figure 4C)
80.0% (8/10) of TNBC tumor tissue samples, respectively (Figure 6A,B). These results suggest that high expression of AnxA2 found in serum samples of TNBC patients is associated with the high expression and phosphorylation of AnxA2 at tyrosine 23 (Tyr23) in tumor tissues of TNBC patients

Summary

Introduction

Breast cancer is the most common and second leading cause of cancer-related deaths among North American women, with the expectation that 276,480 new cases will be diagnosed with 42,170 deaths in 2020 [1]. Breast cancer is a diverse and heterogeneous disease with different phenotypes, prognosis, and responses to treatment [2,3,4,5,6]. Breast cancer is primarily characterized by the expression of estrogen receptor (ER), progesterone receptor (PR), and/or human epidermal growth factor receptor type 2 (HER2) [7,8]. The status of these three markers and other clinicopathological factors such as age, race, menopause status, tumor grade and stage, and lymph node involvement have been identified as prognostic factors that help in making decisions on systemic therapies [6,9]. There is still an urgent need to establish novel noninvasive biomarkers which are easy to detect and valuable for prognostic and diagnostic prediction

Methods

Results

Conclusion