Oscillations occur in diverse areas of cellular biology, from mechanotransduction to circadian control. Their physiological, pathological, and therapeutic significance in breast cancer remains undetermined, and their existence has yet to be described in the key oncogenic signaling pathways. Mathematical modeling lends itself to detailed study of these complex dynamic phenomena. We observed damped oscillations in pERK with approximately 20 minute periodicity in MCF7 breast carcinoma cell lines after stimulation with heregulin or epidermal growth factor (EGF). In order to establish mechanisms by which these oscillations might occur, we used an ordinary differential equation-based mathematical model of MAPK/PI3K signaling to simulate oscillatory behaviour in MAPK signaling. Both modification of feed-forward (HER2 overexpression) and feedback (abrogation of early gene transcription, EGFR phosphorylation by pERK, crosstalk between pAKT and RAF, and binding of pERK with SOS) loops resulted in the emergence of sustained oscillations in phospho-ERK. When these simulations were tested experimentally, MCF7 cells stably transfected with HER2 (MCF7/HER2-18) showed sustained oscillations in pERK when stimulated with heregulin, which were abrogated by inhibition of HER2 heterodimerisation with pertuzumab. Likewise, suppression of transcriptional feedback with cycloheximide resulted in sustained oscillations in pERK of increased amplitude. We have therefore described oscillations in MAPK signalling for the first time in breast cancer cell lines. Since the duration and amplitude of these oscillations is altered both by addition of the HER2 oncogene, and by inhibition of feedback control, the functional consequences of changes in oscillations may have fundamental consequences both in oncogenesis and therapeutic efficacy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-07-02.