<i>PIK3CA</i> Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma

TLDR

Deregulation of the PI3K pathway through PTEN loss or PIK3CA mutation is common in human cancers. The study aimed to examine the relationship between PTEN loss and PIK3CA mutation by assembling a cohort of PTEN‑deficient tumors and a matched PTEN‑intact control group. The authors compared these two cohorts to assess the frequency and associations of PIK3CA mutations relative to PTEN status. PIK3CA mutations were detected in 26 % of 342 breast tumors, were significantly linked to PTEN retention, ER/PR positivity, lymph node metastasis, and ERBB2 overexpression, and were nearly mutually exclusive with PTEN loss, suggesting distinct tumor evolution pathways and early prognostic and therapeutic relevance.

Abstract

Abstract Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit α of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate (PIP3) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.