Gas6 is dispensable for pubertal mammary gland development

Mills, Kylie L.; Gomes, André M. O.; Standlee, Courtney R.; Rojo, Michelle D.; Carmeliet, Peter; Lin, Zhen; Machado, Heather L.

doi:10.1371/journal.pone.0208550

Cited by 9 publications

(10 citation statements)

References 35 publications

(38 reference statements)

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“…Here, we showed that Gas6 is highly expressed in the ductal epithelial cells of normal breast with faint stromal expression ( Fig. 1), which is consistent with our previous studies of the normal murine mammary gland 19 . Epithelial-derived Gas6 protein expression was significantly increased in DCIS, but declined in invasive tumors (Fig.…”

Section: Discussionsupporting

confidence: 92%

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Gas6 expression is reduced in advanced breast cancers

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

“…1a). In support of our previous studies in the mouse mammary gland 19 , Gas6 was highly expressed in the ductal epithelium of normal breast (adjacent normal). Compared to normal tissue, there was a significant increase in Gas6 protein in pure DCIS.…”

Section: Gas6 Expression Declines In Invasive Breast Tumorssupporting

confidence: 89%

Gas6 expression is reduced in advanced breast cancers

et al. 2020

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“…A conundrum raised by our results is that Axl-null animals are able to develop functional mammary glands, yet upon ex vivo transplantation into cleared fat pads of recipient mice the sorted Axl-null epithelial cells showed a significant reduction in the ability to reconstitute the mammary tree. Relatedly, the GAS6-null mouse also develops functional mammary glands ( Mills et al., 2018 ). Knockout of the TAM family member Mer did show a developmental phenotype during post-lactational involution as it was shown necessary for mediating epithelial efferocytosis of apoptotic cells, but AXL and Tyro3 were explicitly not required for that process ( Sandahl et al., 2010 ).…”

Section: Discussionmentioning

confidence: 99%

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

et al. 2020

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Summary The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro . Axl -null mice did not exhibit a strong developmental phenotype, but enrichment of Axl + cells was required for mouse mammary gland reconstitution upon transplantation, and Axl- null mice had reduced incidence of Wnt1- driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

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“…In addition to neoplastic cells, Gas6 is expressed by luminal progenitor and basal cells around the ductal lining of the mammary tissue [ 65 ]. In the bone microenvironment, Gas6 is secreted by osteoblasts that are involved in forming bones [ 66 , 67 , 68 ].…”

Section: Gas6 and Axl Expression In The Tumor Microenvironmentmentioning

confidence: 99%

Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

Tanaka

Siemann

2020

Cancers

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Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specific 6 (Gas6) protein are expressed by a number of host cells. The Gas6/Axl signaling pathway has been implicated in the promotion of tumor cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. As a result, Axl is an attractive, novel therapeutic target to impair multiple stages of tumor progression from both neoplastic and host cell axes. This review focuses on the role of the Gas6/Axl signaling pathway in promoting the immunosuppressive tumor microenvironment, as immune evasion is considered one of the hallmarks of cancer. The review discusses the structure and activation of the Gas6/Axl signaling pathway, GAS6 and AXL expression patterns in the tumor microenvironment, mechanisms of Axl-mediated tumor immune response, and the role of Gas6/Axl signaling in immune cell recruitment.

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Gas6 is dispensable for pubertal mammary gland development

Cited by 9 publications

References 35 publications

Gas6 expression is reduced in advanced breast cancers

Gas6 expression is reduced in advanced breast cancers

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

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