Cancer-associated systemic inflammation is strongly linked with poor disease outcome in cancer patients 1,2. For most human epithelial tumour types, high systemic neutrophil-tolymphocyte ratios are associated with poor overall survival 3 , and experimental studies have demonstrated a causal relationship between neutrophils and metastasis 4,5. However, the cancer cell-intrinsic mechanisms dictating the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Using a panel of 16 distinct genetically engineered mouse models (GEMMs) for breast cancer, we have uncovered a novel role for cancer cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, p53 loss in cancer cells induced secretion of Wnt ligands that stimulate IL-1β production by tumour-associated macrophages, which drives systemic inflammation. Pharmacological and genetic blockade of Wnt secretion in p53-null cancer cells reverses IL-1β expression by macrophages and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a novel mechanistic link between loss of p53 in cancer cells, Wnt ligand secretion and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for cancer patients. 4 Main text To determine how pro-metastatic systemic inflammation is influenced by genetic aberrations in tumours, we studied 16 GEMMs for breast cancer carrying different tissue-specific mutations. These GEMMs represent most subtypes of human breast cancer, including ductal and lobular carcinoma, oestrogen receptor-positive (luminal A), HER2 + , triple-negative and basal-like breast cancer. Because we and others have demonstrated that neutrophils expand systemically and promote metastasis 5-10 , we evaluated circulating neutrophil levels as a marker for systemic inflammation in mammary tumour-bearing mice with end-stage disease. As expected, most tumour-bearing mice displayed an increase in circulating neutrophils as compared to non-tumour-bearing animals (wild-type [WT]) (Fig. 1a). Like the inter-patient heterogeneity in systemic inflammation in human breast cancer 11 , we observed a striking variability in the extent of neutrophilia between the different tumour-bearing GEMMs (Fig. 1a, Extended Data Fig. 1a). We found that the models exhibiting high neutrophil expansion displayed a subset of neutrophils expressing the stem cell marker cKIT (Fig. 1b), indicative of an immature neutrophil phenotype 5. We subsequently searched for commonalities and differences among the 16 GEMMs with regards to high versus low systemic neutrophil levels. Strikingly, mice bearing tumours with a p53 deletion exhibited the most pronounced circulating neutrophil levels (Fig. 1a). The difference in magnitude of systemic inflammation between p53proficient and p...

TRPM7 encodes a Ca 2þ -permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. Cancer Res; 72(16); 4250-61. Ó2012 AACR.

BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.