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[Cancer Research 65, 2554-2559, April 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

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

Lao H. Saal1,4,6, Karolina Holm6, Matthew Maurer4, Lorenzo Memeo2, Tao Su5, Xiaomei Wang5, Jennifer S. Yu2,4, Per-Olof Malmström6, Mahesh Mansukhani2, Jens Enoksson7, Hanina Hibshoosh2,5, Åke Borg6,8 and Ramon Parsons2,3,4,5

1 Integrated Program in Cellular, Molecular, and Biophysical Studies, Departments of 2 Pathology and 3 Medicine, 4 Institute for Cancer Genetics, 5 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York; Departments of 6 Oncology and 7 Pathology, 8 Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

Requests for reprints: Ramon Parsons, Institute for Cancer Genetics, 1150 St. Nicholas Avenue, New York, NY 10032. Phone: 212-851-5278; Fax: 212-851-5256; E-mail: rep15{at}columbia.edu.

Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit {alpha} 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.

Key Words: PTEN • PIK3CA • PI-3 kinase • breast cancer • ERBB2




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