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Gas6 is dispensable for pubertal mammary gland development.

ABSTRACT: Mammary gland development is a complex and dynamic process that occurs mainly postnatally. Ductal elongation and branching morphogenesis are regulated by a plethora of factors, including cytokines, hormones, growth factors and the extracellular matrix. Gas6 is a secreted gamma-carboxylated protein that binds to a family of receptors tyrosine kinase receptors known as the TAMR family (Tyro3, Axl, Mer). Gas6 function in developmental processes has been shown in nervous, reproductive and immune systems. In this study, we found that Gas6 is highly expressed in virgin adult mammary glands but declines during pregnancy and lactation. Specifically, Gas6 is highly expressed in luminal and basal mammary epithelial cells during puberty and adulthood, while TAMR expression is low. Mammary whole mount analysis revealed that Gas6 germline deletion does not impact ductal elongation, branching morphogenesis or terminal end bud formation. Masson's trichrome staining showed that collagen deposition is similar in Gas6-/- mice as compared to wildtype mice. Gas6-/- mammary glands presented an organized luminal and myoepithelial bilayer of cells, and the proportion of mammary stem cells was unchanged in Gas6-/- mammary glands as compared to wildtype. Finally, proliferation of epithelial cells and macrophage number were similar in both groups. These studies suggest that Gas6 is not essential for pubertal mammary gland development in nulliparous mice.

SUBMITTER: Mills KL

PROVIDER: S-EPMC6289431 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Gas6 is dispensable for pubertal mammary gland development.

Mills Kylie L KL Gomes Angelica M AM Standlee Courtney R CR Rojo Michelle D MD Carmeliet Peter P Lin Zhen Z Machado Heather L HL

PloS one 20181211 12

Mammary gland development is a complex and dynamic process that occurs mainly postnatally. Ductal elongation and branching morphogenesis are regulated by a plethora of factors, including cytokines, hormones, growth factors and the extracellular matrix. Gas6 is a secreted gamma-carboxylated protein that binds to a family of receptors tyrosine kinase receptors known as the TAMR family (Tyro3, Axl, Mer). Gas6 function in developmental processes has been shown in nervous, reproductive and immune sys ...[more]

PMID: 30533018

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Project description:IntroductionEpidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD.MethodsPubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis.ResultsHFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-?B activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages.ConclusionsTaken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.

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Gas6 is dispensable for pubertal mammary gland development.

Publications

Gas6 is dispensable for pubertal mammary gland development.

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