PI3K/AKT Suppressor Gene Affects Breast Tumor Growth and Metastasis

A new piece of the molecular puzzle of breast cancer metastasis – the leading cause of breast cancer deaths --appears to have been identified by researchers in Australia. Findings published in the current issue of Cancer Cell ¹ show that a newly-identified lipid phosphatase gene, proline-rich inositol polyphosphate 5-phosphatase, or PIPP (INPP5J), is involved in primary breast tumor initiation and growth.

Together with the oncogene AKT1, their study also implicates PIPP in breast tumor metastasis, reported lead study author Lisa M. Ooms, PhD, of the Department of Biochemistry and Molecular Biology at Monash University in Victoria, Australia.²

Phosphoinositide 3-kinase (PI3K) activates AKT, which is involved in breast cancer cell proliferation and migration, the authors noted. The PI3K signaling pathway is “frequently hyperactivated in breast cancer and represents a significant target for novel therapies,” the authors noted. The new study found that PIPP inhibits PI3K/AKT signaling.

The authors reported that PIPP mRNA expression is reduced in human estrogen receptor (ER)-negative breast cancers, which are associated with poor patient prognosis. PIPP ablation (knock-out) in a mouse model of breast cancer promotes oncogene-driven breast cancer tumorigenesis and tumor growth, but “paradoxically” impairs metastasis, they reported.

Based on these findings, the team has identified PIPP as a PI3K/AKT signaling suppressor.

“The discovery of the new tumor suppressor could have significant implications for the way we treat, manage, and even potentially detect specific subsets of breast cancers that need targeted or specific treatments related to the gene expression profile in which PIPP expression is lost,” said senior study author Professor Christina Mitchell, MBBS, FRACP, FRCPA, PhD, of the Department of Biochemistry and Molecular Biology at Monash University in Victoria, Australia.

Because The Cancer Genome Atlas found no significant genomic alterations in PIPP in breast tumors, the authors suggested that epigenetic mechanisms might well underlie their findings.

The findings “suggest that analysis of PIPP expression in human breast cancers may identify a subset of patients that would benefit from therapies targeting the PI3K signaling pathway,” as well as risk stratification of patients who are at higher risk of developing secondary tumors, the authors concluded.

“Small molecule inhibitors targeting both PI3K and AKT are currently under clinical evaluation,” they noted. “However, notably, there are no AKT isoform-selective compounds that are under development.”

The findings also open the door to the development of drugs that can target primary tumors or slow tumor growth, they concluded.

References:

• Ooms LM, Binge LC, Davies EM, et al. (2015).The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis. Cancer Cell, Aug 10;28(2):155-69.
• Monash University. (2015). Monash study discovers breast cancer metastasis gene.