IP6K2 predicts favorable clinical outcome of primary breast cancer.

The inositol hexakisphosphate kinase (IP6K) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53. A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be.