Oral Presentation ESA-SRB Conference 2015

TGFB1 is a key regulator of mammary gland macrophages during development and tumourigenesis (#122)

Xuan Sun 1 2 , Sarah Robertson 1 2 , Wendy Ingman 1 2 3
  1. Obstetrics and Gynaecology, The University of Adelaide, Adelaide, SA, Australia
  2. Research Centre for Reproductive Health, Robinson Research Institute, Adelaide, South Australia, Australia
  3. Discipline of Surgery, School of Medicine , The Queen Elizabeth Hospital, Adelaide

Macrophages are highly versatile cells capable of diverse roles in development, homeostasis and immunity. Transforming growth factor beta 1 (TGFB1) is a multi-functional cytokine that regulates cell proliferation, apoptosis and immune system responses. In the breast, TGFB1 is mainly produced by mammary epithelium, where it co-localises with macrophages and regulates macrophage functions. This study sought to investigate the role of TGFB-regulated macrophages in mammary gland development and tumourigenesis utilising a double transgenic (Cfms-rtTA x TetO-TgfbrII) mouse model, whereby a dominant negative TGFB receptor is activated specifically in macrophages and attenuates TGFB signalling. Impaired TGFB signalling in macrophages resulted a 50% increase in macrophages invaded into the mammary epithelium, and the abundance of iNOS+ (“M1”) and CCR7+ (“M1”) stromal macrophages was increased by 110% and 37% respectively (p<0.05). Susceptibility to development of mammary gland cancer was investigated by challenging the transgenic mice with DMBA carcinogen. Double transgenic mice with impaired TGFB signalling in macrophages were more resistant to mammary tumour induction compared to control mice, with tumour incidence decreased and tumour latency increased (p<0.05). Immunohistochemical analysis of human non-neoplastic breast tissue revealed that macrophages may be similarly regulated by epithelial cell-derived TGFB1 in humans as they are in mice. There was an inverse relationship between abundance of TGFB1 protein and CD68+ macrophages invaded into mammary epithelium (R2=0.26; p=0.027), and a positive relationship between abundance of TGFB1 and stromal CD206+ (“M2”) macrophages (R2=0.33; p=0.013). These findings suggest that the mammary epithelium of mice and humans directs the phenotype and function of adjacent macrophage populations, and that TGFB1 is a key cytokine in this crosstalk. Specifically, epithelial cell-derived TGFB1 appears to reduce the abundance of “M1” macrophages involved in immune surveillance, and increase the abundance of immune tolerant “M2” macrophages, leading to increased susceptibility to breast cancer.