LAUSR

PI3K-stimulated induction of pentraxin-3 links innate immune signaling with the growth of basal-like breast cancer. Pentraxin-3 promotes growth of stem-like cancers The phosphoinositide 3-kinase (PI3K) pathway is activated in various cancers. Unfortunately, PI3K inhibitors have limited clinical efficacy, particularly in patients with a subtype of breast cancer characterized by cells with stem cell–like properties. Thomas et al. found that an activating mutation in the catalytic α subunit of PI3K enhanced the expression of a gene encoding pentraxin-3, a protein that functions in the innate immune response. Furthermore, an increase in the abundance of pentraxin-3 promoted stem cell–like traits in mammary epithelial and breast cancer cells. The mRNA abundance of PTX3 correlated with poor prognosis of patients with basal-like breast cancer. The findings link innate immune signaling with breast cancer development and suggest that targeting pentraxin-3 may suppress tumor growth in a subset of patients. Basal-like breast cancers (BLBCs) exhibit hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway because of the frequent mutational activation of the PIK3CA catalytic subunit and the genetic loss of its negative regulators PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate-4-phosphatase type II). However, PI3K inhibitors have had limited clinical efficacy in BLBC management because of compensatory amplification of PI3K downstream signaling loops. Therefore, identification of critical PI3K mediators is paramount to the development of effective BLBC therapeutics. Using transcriptomic analysis of activated PIK3CA–expressing BLBC cells, we identified the gene encoding the humoral pattern recognition molecule pentraxin-3 (PTX3) as a critical target of oncogenic PI3K signaling. We found that PTX3 abundance is stimulated, in part, through AKT- and nuclear factor κB (NF-κB)–dependent pathways and that presence of PTX3 is necessary for PI3K-induced stem cell–like traits. We further showed that PTX3 expression is greater in tumor samples from patients with BLBC and that it is prognostic of poor patient survival. Our results thus reveal PTX3 as a newly identified PI3K-regulated biomarker and a potential therapeutic target in BLBC.