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Proximity ligation assays for isoform‐specific Akt activation in breast cancer identify activated Akt1 as a driver of progression
Author(s) -
Spears Melanie,
Cunningham Carrie A,
Taylor Karen J,
Mallon Elizabeth A,
Thomas Jeremy St J,
Kerr Gillian R,
Jack Wilma JL,
Kunkler Ian H,
Cameron David A,
Chetty Udi,
Bartlett John MS
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4022
Subject(s) - akt2 , akt1 , breast cancer , protein kinase b , cancer research , cancer , pi3k/akt/mtor pathway , medicine , gene isoform , phosphorylation , signal transduction , chemistry , biochemistry , gene
The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine‐treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform‐specific activation (phosphorylation) of Akt1 and Akt2 in formalin‐fixed, paraffin‐embedded cell lines and breast cancer tumour tissues in situ . PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14–1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10–1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34–2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32–2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.