An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

By K. Stemke‐Hale, A. González-Angulo, A. Lluch, R. Neve, W. Kuo, M. Davies, M. Carey, Zhi Hu, Y. Guan, A. Sahin and 12 more. Cancer Research, 2008

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Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor–positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor–positive breast cancer.

Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/036d2fbcc9d6ab5233b17e6a94bc91568e7a2235

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Citations in the corpus

Triple-negative breast cancer molecular subtyping and treatment progress (2020, result): “pendency is similar to ER-positive breast cancers, which have a high frequency of PIK3CA mutations [58, 59].”
The mTOR Signalling Pathway in Human Cancer (2012, background): “overexpression or activation of growth factor receptors, such as HER-2 (human epidermal growth factor receptor 2) and IGFR (insulin-like growth factor receptor), mutations in PI3K and mutations/amplifications of AKT [121–123].”
Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer (2009, background): “The importance of PI3Ks in cancer was confirmed by the discovery that the PI3K catalytic subunit α-isoform gene ( PIK3CA ), which encodes p110α, is frequently mutated in some of the most common human tumour”
The emerging mechanisms of isoform-specific PI3K signalling (2010, background): “This was elaborated on in a recent comprehensive analysis of cancer cells carrying mutant PIK3CA , which confirmed that many of these cells exhibit minimal activation of Akt and downstream signallin”
Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. (2009, background): “Compatible with the latter contention, we have shown previously that PIK3CA mutational status is not correlated with AKT phosphorylation in hormone receptor-positive breast cancers or cell lines (12).”
The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing (2015, background): “5% for hormone receptor positive and Her2 positive breast cancers(17-19), perhaps suggesting”
Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis (2018, background): “PIK3CA mutations and gain of copy number of PIK3CA and PTEN loss and PTEN mutations have also been reported to coexist, although PIK3CA, PTEN, AKT1, and PIK3R1 mutations are reported to be mutually exclusive.(230,237,238) Oncogenic PIK3CA mutations are thought to cause dedifferentiation of luminal o”
Artificial intelligence and machine learning in precision and genomic medicine (2021, background): “The combination of proteomics and genomics datasets led to the invention of a new targeted drug in breast cancer (hormone receptor positive), such as an altered PI3K pathway [117].”
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. (2011, background): “All 5 LAR cells lines have activating PIK3CA mutations and are sensitive to the PI3K inhibitor NVP-BEZ235, similar to ER-positive breast cancer in which PIK3CA mutations are common (61, 62).”
NEW STRATEGIES FOR TRIPLE NEGATIVE BREAST CANCER – DECIPHERING THE HETEROGENEITY (2014, background): “The coevolution of PIK3CA mutations with androgen receptor dependency is similar to ER-positive breast cancers frequently containing PIK3CA mutations (36, 37).”