Aims: Activation of the PI3K/Akt signal transduction pathway has been linked to endocrine resistance in tamoxifen treated breast cancer patients. Activation of the PI3K/Akt pathway causes phosphorylation of Bad leading to modulation of cellular apoptosis. The present study was carried out to test the hypothesis that disruption of apoptosis in breast cancer, via Akt activation, is linked with hormone resistance.
Methods: Immunohistochemistry (IHC) was performed on 402 oestrogen receptor (ER) positive breast cancers using antibodies against Bad, pBad (ser 112), Bcl-2, Bcl-xl and Bax.
Results: Bad, pBad (ser 112), Bcl-2 and Bax expression was observed in the cellular cytoplasmic compartment only. Patients, whose tumours had high levels of Bad expression, had a significantly improved disease-free survival when compared to patients whose tumours had low levels of Bad expression (P = 0.049). Activation of the PI3K/Akt pathway by either heregulin or oestrogen had no effect on expression of Bad, Bcl-2, Bax or Bcl-xl. However, heregulin increased pBad (ser 112) expression.
Discussion: Data presented here shows that Bad expression is associated with relapse in tamoxifen-treated breast cancer patients, supporting our hypothesis that the apoptosis pathway is involved in tamoxifen resistance.