PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma.

By L. Saal, K. Holm, M. Maurer, L. Memeo, T. Su, Xiaomei Wang, Jennifer S. Yu, P. Malmström, M. Mansukhani, J. Enoksson and 3 more. Cancer Research, 2005

924 citations recorded by the source corpus.

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 (PIP(3)) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP(3) 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ce6c71c0a88eb4b41a98ed960418bdb108b250d5

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Citations in the corpus

• Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. (2009, background): “The PIK3CA mutation frequencies in the common subtypes are compatible with those frequencies reported in the literature, with the exception of that in claudin-low tumors, which has not been reported (27).”
• Perturbations of the AKT signaling pathway in human cancer (2005, background): “…recently, somatic missense mutations of the PIK3CA gene have been reported in 25–35% of gastric and colorectal carcinomas and glioblastomas (Samuels et al., 2004), as well as in about 25% breast cancer specimens and cell lines, with a similar frequency seen in tumor stages I–IV (Saal et al., 2005).”
• An overview of triple-negative breast cancer (2016, background): “Proteins belonging to the PI3K pathway are frequently affected by mutations in breast carcinomas, and loss of PTEN is a common finding in TNBC, thus leading to increased mTOR activation in the disease [161].”
• Subtle variations in Pten dose determine cancer susceptibility (2010, background): “As PTEN is infrequently lost or mutated at the genomic level in individuals with breast cancer, despite a frequent decrease in the PTEN protein leve”
• PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. (2009, methodology): “PTEN protein expression was evaluated by immunohistochemistry on 3-Am formalin-fixed paraffin-embedded tissue sections as previously reported (16, 18) with some modifications.”
• Current development of mTOR inhibitors as anticancer agents (2006, background): “Although PI3K mutations correlate with ER/PR-overexpression, PTEN loss correlates with the loss of either/or ER/PR, suggesting that breast cancer might follow two distinct patterns of carcinogenesi”
• An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer (2008, background): “PIK3CA and PTEN mutations have been reported to be mutually exclusive in many cancers with a notable exception being endometrial tumors (17, 18).”
• ErbB receptors and signaling pathways in cancer. (2009, background): “Considering breast tumors, somatic activating mutations in Akt [35,36] and the p110a subunit of the PI3K [35,37,38] have been detected in 3–5% and 20–25% of primary breast tumors, respectively.”
• Improved classification of breast cancer by analysis of genetic alterations and gene expression profiling (2011, background): “For this,wemadeuseof samples from twoseries of HER2-overexpressing patients with metastatic breast cancer treated at the Antoni van Leeuwenhoek Hospital (n = 34) and the M.D. Anderson Cancer Center (n = 21).”
• PI3K pathway alterations in cancer: variations on a theme (2008, neutral): “Similarly, Saal et al. (2005) identify 2 (0.7”
• PD-L1 Expression in Triple Negative Breast Cancer (2014, neutral): “Furthermore, PTEN loss is correlated with ER/PR–negative tumors (17).”
• Oncogenic mutations of PIK3CA in human cancers. (2004, background): “were the first group to propose definitive clinicopathological correlates to PIK3CA mutations in breast cancer (Saal et al. 2005).”