Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC190
Orai3 contributes to breast cancer development through c-Myc oncogene pathway activation
M. Faouzi1, F. Hague1, P. Kischel1, N. Benzerdjeb1,2, H. Sevestre1,2, H. Ouadid-Ahidouch1, A. Ahidouch1,3
1. Laboratoire de Physiologie Cellulaire et Moléculaire JE2530, Amiens, France. 2. Service d’Anatomie Pathologique, CHU d'Amiens, Amiens, France. 3. Laboratoire de Physiologie animale, Faculté des Sciences, Université Ibn-Zohr, Agadir, Morocco.
Considerable advances in the molecular understanding of human breast cancer (BC) have emerged during the last decades. However, BC remains, at the dawn of the third millennium, one major public health problem. The main goal of scientists is to develop more efficient drugs targeting proteins involved in regulation of cell proliferation and/or apoptosis. In this context, one of the most promising signaling pathways to target for cancer therapy is the c-Myc pathway (Vita and Henriksson, 2006). In BC, several studies show that 50 to 100% of BC cases present increased levels of c-Myc proteins (Liao and Dickson, 2000). The importance of c-Myc as a potential therapeutic target is due to its involvement as a key actor in G1 phase progression and G1/S transition. The newly discovered calcium channels Orai are known for their pathophysiological roles (Feske, 2010). Nevertheless, their expression and role in BC has only recently emerged (Yang et al., 2008; Faouzi et al., 2011). We have reported that Orai3 channels are overexpressed in more than 70% of BC biopsies (all tissue samples obtained from surgery, and both tumour and normal tissues were taken from the same operative specimen). We have also shown that these channels are involved in proliferation, cell cycle progression and survival of BC cells by regulating the G1 phase and G1/S transition regulator proteins (Faouzi et al., 2011). The importance of these channels is highlighted by the fact that their described role in BC cells seems to be specific to cancer status, since their downregulation does affect neither cell proliferation, nor cell survival in normal breast cells. On the basis of the whole reported data, we hypothesized that Orai3 channels could be upstream regulators of the c-Myc pathway. Thus, we investigated the role of c-Myc in the Orai3-induced proliferation and cell cycle progression in BC cells compared to normal breast cells. Our results showed that Orai3 silencing reduced both c-Myc expression and activity levels in BC cells only. Simultaneous downregulation of both Orai3 channels and c-Myc protein had no additive or synergic effects on either BC cell proliferation or cell survival. One of the known pathways regulating c-Myc protein expression and activity is the MAP Kinase pathway. We therefore investigated the effect of Orai3 downregulation on ERK1/2 phosphorylation. Our results showed that the phosphorylation level of ERK1/2 significantly decreased when Orai3 channels were downregulated. Finally, using q-PCR and Tissue microarray, we evaluated the expression levels of Orai3 channels and c-Myc oncogene in BC biopsies, and found that expression levels of these two actors were positively correlated. To conclude, our results suggest that Orai3 channels are one of the upstream regulators of the oncogenic c-Myc pathway that constitue key players in BC development.
Where applicable, experiments conform with Society ethical requirements