Upregulated Annexin A1 promotes cellular invasion in triple-negative breast cancer

Abstract

Abstract. Annexin A1 (ANXA1) is a calcium-dependent phospholipid-linked protein, involved in anti-inflammatory effects, regulation of cellular differentiation, proliferation and apoptosis. While many studies have investigated the ANXA1 expression in various tumor types, the role of ANXA1 is not fully understood. Therefore, in the present study, we evaluated the ANXA1 expression in 211 breast cancer patients and compared the levels with clinicopathological factors. ANXA1 was positively expressed in 31 (14.7%) of the 211 cases in our cohort, and these positive cases were associated with triple-negative breast cancer (TNBC) (P=0.007) and venous invasion (P=0.028). The in vitro cell experiment found that the MDA-MB-231 cell line, which is a TNBC cell line, highly expressed ANXA1. Using this cell line, the functional role of ANXA1 in breast cancer was revealed and the knockdown of ANXA1 by specific siRNA demonstrated a significant reduction in cellular invasion. Further experiments indicated that ANXA1 was induced by hypoxia with hypoxia-inducible factor-1α induction. These results suggested that ANXA1, which enhanced breast cancer invasion and metastasis under hypoxia, were significantly associated with the worst patient outcome. This is particularly noted in TNBC, the group of breast cancer with the worst outcome for which new therapeutic implications are required. IntroductionBreast cancer is a leading cause of cancer related mortality among females worldwide and its incidence and mortality rate have been increasing throughout the recent years (1). The treatment of breast cancer has progressed over the past three decades with the development of the combination of chemotherapy, endocrine therapies and human epidermal growth factor receptor 2 (HER2)-targeted therapies (2-5). However, triple-negative breast cancer (TNBC), which is defined by the lack of the estrogen receptor (ER), the progesterone receptor (PgR) and HER2 expression, has not fully benefited from such advances in treatment. Therefore, patients with TNBCs are currently categorized as a sub group with the worst possible outcome. Although recent progress in gene sequencing technology has revealed the genetic profile of breast cancer including that of TNBC, the effort to understand breast cancer based on the diverse view from a more inclusive perspective is still needed (6-8).Annexin A1 (ANXA1) is a 37-kDa calcium-dependent phospholipid-linked protein belonging to the annexin superfamily and it is related to anti-inflammatory effects, regulation of cellular differentiation, proliferation and apoptosis (9-11). However, through those functions, ANXA1 is involved in tumorigenesis and the pivotal role of ANXA1 is not clearly understood. One of the main reasons for this is due to the fact that the functional role of ANXA1 in malignant tumors is quite different depending on the cancer type, such as head-and-neck, esophageal, gastric, colorectal, pancreatic, hepatic and prostate cancer (12-19). While ANXA1 is highly expressed in malignant tumors (20,21), some stu...

Identification of specific biomarkers for gastric adenocarcinoma by ITRAQ proteomic approach

“…Previous reports suggest that ANXA1 is involved in membrane aggregation, cell matrix interaction, vesicle transport, phagocytosis, proliferation, apoptosis, inflammation and cell transformation29. ANXA1 expression is up-regulated in breast cancer30, hepatocellular carcinoma31, melanoma32, and rectal cancer, but down regulated in nasopharyngeal carcinoma33 and cervical cancer34. In breast cancer, ANXA1 expression is associated with BRCA1/2 mutations35.…”

Annexin/S100A Protein Family Regulation through p14ARF-p53 Activation: A Role in Cell Survival and Predicting Treatment Outcomes in Breast Cancer

“…Dysregulation of the expression of individual annexins has been associated with breast cancer development and poor prognosis, and modulation of calcium signaling by p53 has been associated with lack of sensitivity to chemotherapy and radiotherapy [20, 22, 27, 45–49]. Pre-clinical validation of prognostic gene candidates in a large independent cohort is a prerequisite for the development of robust biomarkers.…”

“…However the literature on dysregulation of annexin protein expression in breast cancer is contentious. Deregulation of individual annexins and S100A proteins have been associated with malignant transformation [22–26], tumor invasion [27–29], metastasis, angiogenesis and drug resistance [20, 30, 31], the effect being dependent on breast cancer sub-type.…”

Annexin A1 is upregulated in p53-positive gastric cancer

“…Therefore, the ectopic expression of ANXA1 is thought to drive various cancer developments 2,3) . We previously reported that a breast cancer case of positive ANXA1 expression by immunohistochemical (IHC) staining was frequently identified in triple-negative breast cancer (P = 0.007) and was associated with positive venous invasion (P = 0.028) 4) . We also reported that ANXA1 enhanced breast cancer invasion and metastasis under hypoxia in in vitro cell experiments, indicating that ANXA1 was apparently associated with breast cancer progression 4) .…”

“…We previously reported that a breast cancer case of positive ANXA1 expression by immunohistochemical (IHC) staining was frequently identified in triple-negative breast cancer (P = 0.007) and was associated with positive venous invasion (P = 0.028) 4) . We also reported that ANXA1 enhanced breast cancer invasion and metastasis under hypoxia in in vitro cell experiments, indicating that ANXA1 was apparently associated with breast cancer progression 4) . In addition, we stated that colon cancer cases with positive ANXA1 expression by IHC staining were associated with lymphatic invasion (P = 0.011), venous invasion (P = 0.023), and lymph node metastasis (P = 0.042) 5) .…”