Abstract
Growth arrest-specific gene 6 (Gas6) is a cytokine that binds to receptor tyrosine kinases Tyro3, Axl, and Mer. Numerous studies have suggested that macrophage-derived Gas6 interacts with Axl to promote cancer progression, and Axl has been associated with poor clinical outcome. However, the expression and relevance of Gas6 in human breast cancer patients has not been studied. Analysis of tissue microarrays showed that Gas6 was highly expressed in ductal carcinoma in situ (DCIS) but markedly decreased in invasive breast cancer. Gas6 and Axl were weakly correlated, suggesting that their functions may not exclusively rely on each other. Analyses of publicly available databases showed significantly improved overall and relapse-free survival in patients with high Gas6 mRNA, particularly in luminal A breast cancers. These findings indicate that tumor-derived Gas6 is not overexpressed in invasive breast cancer, and may not be a negative prognostic factor in human breast cancer.
Highlights
Gas[6] is a vitamin K-dependent cytokine that binds to a family of receptor tyrosine kinases that includes Tyro[3], Axl, and Mer (TAMR family), with 100–1000 times higher affinity for Axl[1,2]
We previously reported that Gas[6] was expressed in macrophages and pre-invasive epithelial cells of ductal carcinoma in situ (DCIS)[18], the non-obligatory precursor of invasive ductal carcinoma (IDC)
We stained two tissue microarrays (TMAs) (Table 1) with an antibody that recognizes human Gas[6], and scored epithelial staining based on intensity and the number of stained cells
Summary
Gas[6] is a vitamin K-dependent cytokine that binds to a family of receptor tyrosine kinases that includes Tyro[3], Axl, and Mer (TAMR family), with 100–1000 times higher affinity for Axl[1,2]. Gas6/TAMR signaling is a critical component of the innate immune response, functions in phagocytic clearance of apoptotic cells and is an important thrombosis factor. Gas[6] was shown to modulate different cellular events such as proliferation, survival and invasion in vitro[3,4,5]. Axl signaling promotes tumor cell survival and invasion, such as osteosarcoma[6], hepatocellular carcinoma[7], renal cell carcinoma[8], and lung cancer[9]. Studies using mouse models have shown that macrophage-derived Gas[6] may have a tumor-promoting role in cancer progression[12]. Other studies revealed Gas6-independent functions of Axl including regulation of epithelial–mesenchymal–transition and breast cancer metastasis[10,13,14]. Axl can be activated by other RTKs, including EGFR and VEGFR2, and has been associated with resistance to targeted therapies in lung, pancreatic, and breast cancers[15,16,17]
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