Metastatic breast cancer cells have reduced calcium and actin response after ATP-P2Y2 signaling

The tumor microenvironment and wound healing, both contain high concentrations of the extracellular, adenosine triphosphate (ATP) compared to normal tissue. P2Y2, an ATP-activated purinergic receptor, is typically associated with pulmonary and neurological signaling. Here we report its importance in breast epithelial cell signaling and the alterations in metastatic breast cancer. P2Y2 signaling causes increased intracellular calcium (Ca2+) in non-tumorigenic breast epithelial cells, leading to actin re-localization, while the metastatic cells had significantly decreased Ca2+ changes and no actin alterations. The increase in Ca2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization in non-tumorigenic cells. Furthermore, the lack of Ca2+ and actin changes in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in patients. This study begins to elucidate the rapid changes that occur after elevated intracellular Ca2+ in breast epithelial cells and how metastatic breast cancer cells have adapted to evade a normal cellular response. ### Competing Interest Statement SSM is an employee of the VA Maryland Health Care System. The views reported in this paper do not reflect the views of the Department of Veterans Affairs or the United States Government. The PTEN-/-; cells are licensed by Horizon Discovery Ltd. (Cambridge, UK), MIV receives compensation from the sale of these cells. At the time of this publication, AAG is a contracted employee of AbbVie inc.