Abstract
Patient selection for PI3K-targeted solid cancer treatment was based on the PIK3CA/PTEN mutational status. However, it is increasingly clear that this is not a good predictor of the response of breast cancer cells to the anti-proliferative effect of PI3K inhibitors, indicating that isoform(s) other than p110α may modulate cancer cells sensitivity to PI3K inhibition. Surprisingly, we found that although no mutations in the p110δ subunit have been detected thus far in breast cancer, the expression of p110δ becomes gradually elevated during human breast cancer progression from grade I to grade III. Moreover, pharmacological inactivation of p110δ in mice abrogated the formation of tumours and the recruitment of macrophages to tumour sites and strongly affected the survival, proliferation and apoptosis of grafted tumour cells. Pharmacological inactivation of p110δ in mice with defective macrophages or in mice with normal macrophages but grafted with p110δ-lacking tumours suppressed only partly tumour growth, indicating a requisite role of p110δ in both macrophages and cancer cells in tumour progression. Adoptive transfer of δD910A/D910A macrophages into mice with defected macrophages suppressed tumour growth, eliminated the recruitment of macrophages to tumour sites and prevented metastasis compared with mice that received WT macrophages further establishing that inactivation of p110δ in macrophage prevents tumour progression. Our work provides the first in vivo evidence for a critical role of p110δ in cancer cells and macrophages during solid tumour growth and may pave the way for the use of p110δ inhibitors in breast cancer treatment.
Highlights
Introduction The classIA subset of phosphoinositide-3 kinases (PI3Ks) are heterodimers made up of a regulatory subunit and a 110 kDa catalytic subunit (p110α, p110β or p110δ)[1,2,3]
Given that no somatic mutations of PIK3CD gene encoding the PI3K p110δ have been reported in breast cancer[6,14,15,16,17], we sought to explore the p110δ protein expression during human breast cancer progression by immunohistochemistry in a collection of human breast carcinomas of grade I (n = 20), grade II (n = 20) and grade III (n = 20). p110δ was detected as cytoplasmic staining in all carcinomas and in some cases p110δ was detected as focal staining and in deposits (Fig. 1a)
Double immunostaining of human breast carcinomas of grade III for p110δ and CD68 revealed strong p110δ staining in macrophages (CD68+ cells) (Fig. 1d), which had an intensity similar with that measured in cancer cells (Fig. 1e)
Summary
Introduction The classIA subset of phosphoinositide-3 kinases (PI3Ks) are heterodimers made up of a regulatory subunit and a 110 kDa catalytic subunit (p110α, p110β or p110δ)[1,2,3]. The p110α isoform is a well-known oncoprotein since gain-of-function mutations in PIK3CA gene are present in a wide variety of human solid tumours[4,5,6,7]. The p110β isoform has been implicated in platelet biology, thrombosis[8] and in certain cancers, especially in tumour cells lacking phosphatase and tensin homolog on chromosome 10 (PTEN)[9,10,11,12,13]. The gene encoding p110δ is rarely mutated in cancers[6,14,15,16,17,18,19,20,21], and because of the preferential expression of p110δ in leukocytes this isoform has been mostly considered as a target in immunity and inflammation[22,23,24]. A promising role of the PI3K p110δ has been suggested in cancers of nonhaematopoietic origin[29]; the role of p110δ in breast cancer in vivo is poorly explored
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