Xuan Sun1,2, Sarah M Bernhardt1,2, Danielle J Glynn1,2, Leigh J Hodson1,2, Lucy Woolford3, Andreas Evdokiou1, Cong Yan4, Hong Du4, Sarah A Robertson2,5, Wendy V Ingman6,7,8. 1. Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia. 2. Robinson Research Institute, University of Adelaide, Adelaide, Australia. 3. School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia. 4. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA. 5. Adelaide Medical School, University of Adelaide, Adelaide, Australia. 6. Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia. wendy.ingman@adelaide.edu.au. 7. Robinson Research Institute, University of Adelaide, Adelaide, Australia. wendy.ingman@adelaide.edu.au. 8. Discipline of Surgery, The Queen Elizabeth Hospital, DX465702, 28 Woodville Rd., Woodville, 5011, Australia. wendy.ingman@adelaide.edu.au.
Abstract
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 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. CONCLUSIONS: 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.
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 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. CONCLUSIONS: 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.
Authors: Jenean O'Brien; Traci Lyons; Jenifer Monks; M Scott Lucia; R Storey Wilson; Lisa Hines; Yan-gao Man; Virginia Borges; Pepper Schedin Journal: Am J Pathol Date: 2010-01-28 Impact factor: 4.307
Authors: Angela Cox; Alison M Dunning; Montserrat Garcia-Closas; Sabapathy Balasubramanian; Malcolm W R Reed; Karen A Pooley; Serena Scollen; Caroline Baynes; Bruce A J Ponder; Stephen Chanock; Jolanta Lissowska; Louise Brinton; Beata Peplonska; Melissa C Southey; John L Hopper; Margaret R E McCredie; Graham G Giles; Olivia Fletcher; Nichola Johnson; Isabel dos Santos Silva; Lorna Gibson; Stig E Bojesen; Børge G Nordestgaard; Christen K Axelsson; Diana Torres; Ute Hamann; Christina Justenhoven; Hiltrud Brauch; Jenny Chang-Claude; Silke Kropp; Angela Risch; Shan Wang-Gohrke; Peter Schürmann; Natalia Bogdanova; Thilo Dörk; Rainer Fagerholm; Kirsimari Aaltonen; Carl Blomqvist; Heli Nevanlinna; Sheila Seal; Anthony Renwick; Michael R Stratton; Nazneen Rahman; Suleeporn Sangrajrang; David Hughes; Fabrice Odefrey; Paul Brennan; Amanda B Spurdle; Georgia Chenevix-Trench; Jonathan Beesley; Arto Mannermaa; Jaana Hartikainen; Vesa Kataja; Veli-Matti Kosma; Fergus J Couch; Janet E Olson; Ellen L Goode; Annegien Broeks; Marjanka K Schmidt; Frans B L Hogervorst; Laura J Van't Veer; Daehee Kang; Keun-Young Yoo; Dong-Young Noh; Sei-Hyun Ahn; Sara Wedrén; Per Hall; Yen-Ling Low; Jianjun Liu; Roger L Milne; Gloria Ribas; Anna Gonzalez-Neira; Javier Benitez; Alice J Sigurdson; Denise L Stredrick; Bruce H Alexander; Jeffery P Struewing; Paul D P Pharoah; Douglas F Easton Journal: Nat Genet Date: 2007-02-11 Impact factor: 38.330