Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) has a poor outcome compared to other breast cancer subtypes, and new therapies that target the molecular alterations driving tumor progression are needed. Annexin A1 is an abundant multi-functional Ca2+ binding and membrane-associated protein. Reported roles of Annexin A1 in breast cancer progression and metastasis are contradictory. Here, we sought to clarify the functions of Annexin A1 in the development and progression of TNBC. The association of Annexin A1 expression with patient prognosis in subtypes of TNBC was examined. Annexin A1 was stably knocked down in a panel of human and murine TNBC cell lines with high endogenous Annexin A1 expression that were then evaluated for orthotopic growth and spontaneous metastasis in vivo and for alterations in cell morphology in vitro. The impact of Annexin A1 knockdown on the expression of genes involved in mammary epithelial cell differentia tion and epithelial to mesenchymal transition was also determined. Annexin A1 mRNA levels correlated with poor patient prognosis in basal-like breast tumors and also in the basal-like 2 subset of TNBCs. Unexpectedly, loss of Annexin A1 expression had no effect on either primary tumor growth or spontaneous metastasis of MDA-MB-231_HM xenografts, but abrogated the growth rate of SUM149 orthotopic tumors. In an MMTV-PyMT driven allograft model of breast cancer, Annexin A1 depletion markedly delayed tumor formation in both immuno-competent and immuno-deficient mice and induced epithelial to mesenchymal transition and upregulation of basal markers. Finally, loss of Annexin A1 resulted in the loss of a discrete CD24+/Sca1− population containing putative tumor initiating cells. Collectively, our data demonstrate a novel cell-autonomous role for Annexin A1 in the promotion of tumor-forming capacity in a model of human breast cancer and suggest that some basal-like TNBCs may require high endogenous tumor cell Annexin A1 expression for continued growth.

A therapeutic antibody targeting annexin-A1 inhibits cancer cell growth in vitro and in vivo

“…This investigation corroborates several previous observations, including those which demonstrated ANXA1 expression in the metastatic TNBC cell line MDA-MB-231 was linked to enhanced cell proliferation and cell cycle transition [ 16 ] and that a decrease in cell proliferation was associated with G 1 phase cell cycle arrest following ANXA1 knockdown via siRNA in pancreatic cancer cell lines [ 15 , 34 , 35 ].…”

“…To validate the efficacy of MDX-124 in vivo, a syngeneic model of TNBC was chosen. This tumour type is well-documented as expressing high levels of ANXA1 which correlates with poorer survival [ 15 , 34 ]. Furthermore, since a syngeneic model has a fully functioning immune system, both direct and immune-mediated anti-tumour activity caused by ANXA1-targeted therapy can be observed.…”

Lysine Acetylome of Breast Cancer-Derived Small Extracellular Vesicles Reveals Specific Acetylation Patterns for Metabolic Enzymes

“…Therefore, this protein has been proposed as a potential EV biomarker for glioblastoma. In a model of human BC, ANXA1 can promote tumor-formation, and it has been suggested that some basal-like TNBCs may require high endogenous tumor cell Annexin A1 expression for continued growth [ 70 ]. In addition, ANXA1 has been suggested to be a useful prognostic marker in HER-2+ BC patients [ 71 ].…”

Glioma stem cell signature predicts the prognosis and the response to tumor treating fields treatment

“…Among the 11 genes with risk scores, ANXA1, encoding a membrane‐localized protein, plays an important role in stem cell maintenance and growth 71 . Johnstone et al indicated that ANXA1 was required for cancer initiation and cancer stem cell (CSC) maintenance in breast cancer 72 . Geary et al demonstrated that fibroblast‐secreted ANXA1 induced prostate tumor cells to gain stem‐cell‐like traits 73 .…”

“… 71 Johnstone et al indicated that ANXA1 was required for cancer initiation and cancer stem cell (CSC) maintenance in breast cancer. 72 Geary et al demonstrated that fibroblast‐secreted ANXA1 induced prostate tumor cells to gain stem‐cell‐like traits. 73 Insulin‐Like Growth Factor Binding Protein 2, encoded by IGFBP2 gene, is highly expressed in GSCs‐high‐risk gliomas.…”