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...

The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor.

The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit-but it is not curative. This Perspectives article describes the different ways through which cancer cells can become resistant to enzalutamide, such as AR truncation and other mutations, as well as by-pass of the AR dependence of prostate cancer cells through expression of the glucocorticoid receptor. The clinical relevance of these mechanisms and emerging questions concerning new therapeutic regimens in the treatment of metastatic CRPC are being discussed.

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.