Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice. A transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H&E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68. Attenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages. TGFB acts on macrophage populations in the mammary gland to reduce their abundance and dampen the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.

中文翻译：

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巨噬细胞中 TGFB 信号减弱可降低小鼠对 DMBA 诱导的乳腺癌的易感性


转化生长因子β1 (TGFB1) 是一种多功能细胞因子，通过内分泌、旁分泌和自分泌机制调节乳腺发育和癌症进展。 TGFB1还在肿瘤的发生和进展中发挥作用，其表达增加与乳腺癌风险增加相关。巨噬细胞是 TGFB1 作用的关键靶细胞，在肿瘤发生中也发挥着至关重要的作用。然而，TGFB 调节的巨噬细胞在乳腺中的确切作用尚不清楚。本研究调查了巨噬细胞中减弱的 TGFB 信号传导对小鼠乳腺发育和乳腺癌易感性的影响。生成了转基因小鼠模型，其中显性失活 TGFB 受体在巨噬细胞中被激活，进而减弱巨噬细胞群体中的 TGFB 信号传导途径。通过整体和 H&E 分析评估乳腺的形态变化，并通过免疫组织化学分析巨噬细胞的丰度和表型。另一组小鼠接受致癌物 7,12-二甲基苯并（a）蒽（DMBA）治疗，并每周监测肿瘤的发展。还对人类非肿瘤性乳腺组织进行了免疫组织化学评估，以确定潜在的 TGFB1 和巨噬细胞标记物 CD68。 TGFB信号传导的减弱导致动情期乳腺中肺泡上皮百分比的增加和巨噬细胞丰度的增加。巨噬细胞的表型也发生了改变，炎症巨噬细胞标志物 iNOS 和 CCR7 分别增加了 110% 和 40%。在 TGFB 信号减弱的小鼠中，观察到 DMBA 诱导的乳腺肿瘤发病率显着降低，无瘤生存期延长。 在人类非肿瘤性乳腺组织中，潜在的 TGFB1 蛋白与 CD68 阳性巨噬细胞之间存在显着的负相关关系。 TGFB 作用于乳腺中的巨噬细胞群，减少其丰度并抑制炎症表型。巨噬细胞中的 TGFB 信号传导可能通过抑制巨噬细胞的免疫监视活动来增加乳腺癌的易感性。