- Paper Report
- Open Access
AKT signalling implicated in failure of endocrine therapy
- Julia MW Gee1
© Biomed Central Ltd 2002
- Received: 14 March 2002
- Accepted: 18 March 2002
- Published: 1 December 2002
- AKT, breast cancer, endocrine resistance, phosphorylation, survival
Acquisition of endocrine resistance is a persistent problem in oestrogen receptor (ER) positive breast cancer. This phenomenon is likely to be underpinned by signalling mechanisms that enhance cell survival and proliferation. PI3 kinase/AKT signalling, which lies downstream of tyrosine kinase receptors including c-erbB2, can phosphorylate ER in a hormone independent manner and protect breast cancer cells from tamoxifen-induced apoptosis in vitro (see Additional information ). However, the contribution of this pathway to endocrine resistance in vivo is currently unknown. This immunocytochemical study begins to address the impact of AKT protein and its phosphorylation (pAKT) in 93 breast cancer patients treated with endocrine therapy, monitoring these parameters versus tumour clinicopathology and disease-free survival.
In total, 54% of tumours proved pAKT positive. pAKT was an independent predictor of distant recurrence, with a fivefold increased risk for pAKT positive patients. There was no parallel prognostic value for the AKT protein. pAKT was not associated with ER, PgR, bcl-2, c-erbB2, nodal status or tumour size. However, pAKT directly correlated with stromal heregulin ?1 content, perhaps confirming paracrine influences driving AKT signalling. An inverse association was noted with S-phase fraction (SPF). Further analysis revealed that a low SPF was prognostically favourable only when tumours were pAKT negative, the authors suggested that pAKT may promote distant relapse by a cell survival (rather than proliferative) mechanism. The authors conclude that AKT activation may have prognostic relevance in breast cancer.
Clinical samples, flow cytometry, immunohistochemistry, phospho-specific antibody
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