posters International Association for Breast Cancer Research 2014

Null mutation in C1q impairs tumourigenesis in MMTV-PyMT and DMBA-induced mammary cancer mouse models (#79)

Siti Noor Din 1 2 , Danielle Glynn 1 2 , Leigh Hodson 1 2 3 , Sarah Robertson 1 2 , Wendy Ingman 1 2 3
  1. Robinson Research Institute, Adelaide, SA, Australia
  2. Discipline Obstetrics & Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia
  3. Discipline Surgery, School of Medicine, University of Adelaide, Adelaide, SA, Australia

The complement protein C1q promotes rapid macrophage-mediated clearance of dying cells and tolerance to self antigens. mRNA encoding C1q is a key gene upregulated during mammary gland regression, and we hypothesize that this complement protein promotes mammary gland tumourigenesis through induction of tolerance to tumour antigens. We have investigated the role of C1q in normal mammary gland development, hormone-mediated regression, and in tumour development using two different mammary tumour mouse models together with C1q null mice. In the absence of C1q, mammary gland development proceeds normally during puberty, with similar abundance of terminal end buds and rate of epithelial cell proliferation at 6 weeks of age compared to C57/BL6 wildtype control mice. However, deficiency in C1q perturbed mammary gland regression, with 30% increased number of ductal branch points 24 hours following progesterone receptor antagonist RU486-induced epithelial cell apoptosis in C1q null mice compared to controls (n=7-11;p=0.026). MMTV-PyMT (background strain C57/Bl6) transgenic mice were crossed with C1q null mice and monitored weekly from 6 weeks by palpation to determine tumour latency, and mammary tumours dissected to assess total tumour burden. Tumour burden was decreased in MMTV-PymT/C1q null mice by 2-fold at both 15 weeks (n=11-13;p=0.031) and 18 weeks (n=27;p=0.031) of age compared to MMTV-PyMT/wildtype mice. Tumour latency was increased by 1 week in MMTV-PyMT/C1q null compared to MMTV-PyMT/wildtype mice (p=0.012, Kaplan-Meier test). Carcinogen-induced mammary tumourigenesis was also investigated in mice administered 7,12-dimethylbenz[a]anthracene (DMBA) by oral gavage for 6 weeks. DMBA-treated C1q null mice were highly resistant to mammary tumourigenesis, with tumours detected in only 2 of 20 mice over the 30 week monitoring period, compared to 10 of 20 DMBA-treated control mice (p=0.02, Kaplan-Meier test). These findings suggest that C1q promotes tissue remodeling and clearance of dying cells during mammary gland regression and increases mammary cancer susceptibility and tumour development.