Attenuated TGFB signalling in macrophages decreases susceptibility to DMBA-induced mammary cancer in mice

作者：Xuan Sun, Sarah M. Bernhardt, Danielle J. Glynn, Leigh J. Hodson, Lucy Woolford, Andreas Evdokiou, Cong Yan, Hong Du, Sarah A. Robertson, Wendy V. Ingman · 发表于：Breast Cancer Research · 年份：2021 · DOI：10.1186/s13058-021-01417-8 · 被引用次数：33 · 研究领域：TGF-β signaling in diseases、Immune cells in cancer、Cancer Cells and Metastasis

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ab...