# Non-redundant roles of the phosphoinositide phosphatases PTEN and PIPP in PI3K/AKT signaling in breast cancer

## TL;DR

This study shows that PTEN and PIPP, two enzymes that regulate cell signaling, have unique roles in preventing breast cancer progression, especially when both are lost.

## Contribution

The study reveals non-redundant, cooperative roles of PTEN and PIPP in suppressing breast cancer in mice and humans.

## Key findings

- Loss of PIPP increases AKT signaling and cell proliferation in Pten+/− mice.
- Combined PIPP/PTEN loss in breast cancer cells boosts AKT activity and proliferation.
- Human breast cancers with combined PIPP/PTEN loss show reduced survival.

## Abstract

Phosphoinositide 3-kinase (PI3K) signaling is hyperactivated in ~70% of breast cancers via mutations in oncogenes including PIK3CA or inactivation/depletion of phosphoinositide (PI)-phosphatases. Generation of PI(3,4,5)P3 by PI3K activates many downstream effectors, including AKT, that induce cellular proliferation in breast cancer. In this context PI(3,4,5)P3 is tightly regulated by PI-phosphatases, including the tumor suppressor PTEN and inositol polyphosphate 5-phosphatases such as PIPP/INPP5J. PTEN and PIPP dephosphorylate PI(3,4,5)P3 to form different lipid products, thereby individually regulating AKT activation. PI3K/AKT signaling is complex and the functional interplay between these PI-phosphatases in suppressing this pathway in vivo is unknown. Here, we utilize experimental models of breast cancer, both dependent and independent of PIK3CA mutation. Pipp ablation in Pten+/− mice increases mammary AKT signaling and cell proliferation, associated with increased hyperplasia and ductal thickening, characteristics linked with mammary epithelial cell transformation. In breast cancer cell lines, combined PIPP/PTEN knockdown increases AKT signaling and cell proliferation, independent of mutant PIK3CA, above any single PI-phosphatase knockdown. Notably, combined PIPP/PTEN loss is observed in a subset of human breast cancers, associated with reduced survival. Collectively, these findings support a model whereby loss of PIPP constitutes a co-operative step towards breast cancer progression in the context of PTEN deficiency.

Experimental models of breast cancer reveal the phosphoinositide-phosphatases PIPP and PTEN play non-redundant roles in suppressing mouse mammary epithelial cell transformation, and disease progression in a subset of human breast cancers.