An investigation of responsiveness to PI3K inhibition in breast cancer cells expressing high levels of androgen receptor

Introduction: Approximately 75% of breast cancers express androgen receptor (AR). There is conflicting evidence regarding the role of androgen signalling and breast cancer survival; a number of studies suggest a protective function but, more recently, AR has been shown to drive oestrogen receptor (ER) gene expression in ER-negative apocrine (AR positive, triple negative) breast cancer. This concept is echoed by a number of studies that have focused on the oncogenic potential of the AR. In this study, we evaluated responsiveness to PI3K inhibition in a series of breast cancer cell lines expressing varying levels of AR.

Methods: IC50 values for the pan-class I PI3K inhibitor BEZ235 were established in a range of breast cancer cells in vitro. BEZ235 inhibits phosphorylation of Akt and also blocks the mTOR pathway. MTS assays were optimised and suitable drug concentrations were then evaluated. Endocrine-sensitive (MCF7) and -resistant (LetR, ZR75.1) cell lines were assessed.

Results: MCF7 cells had an IC50 of 0.01031M, ZR75.1 cells had an IC50 of 0.001064M, and LetR cells had an IC50 of 0.001826M.

Conclusion: Low-AR expression MCF7 cells were found to be much less sensitive to PI3K inhibition than the high-AR cell lines. AR could be used to identify endocrine-resistant patients who would benefit from second-line PI3K inhibitor therapy.