Disruption of P2Y2 signaling promotes breast tumor cell dissemination by reducing ATP-dependent calcium elevation and
Abstract:
The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here we report its role and importance in breast epithelial cell signaling and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular Ca 2+ in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca 2+ responses. The non-tumorigenic cells respond to increased Ca 2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca 2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca 2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca 2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.
Insights
Breast cancer cells evade a key signaling pathway involving adenosine triphosphate (ATP) and the P2Y2 receptor. This evasion, marked by reduced calcium responses and actin mobilization, correlates with poorer patient survival.
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- The tumor microenvironment and wound healing exhibit high extracellular adenosine triphosphate (ATP) levels.
- P2Y2 receptor, an ATP-activated purinergic receptor, is crucial in various cell signaling pathways.
- Its role in breast epithelial cells and metastatic breast cancer remains under investigation.
Purpose of the Study:
- To investigate the role and significance of P2Y2 receptor signaling in breast epithelial cells.
- To understand how this signaling is altered in metastatic breast cancer.
- To elucidate the link between P2Y2 receptor expression and patient survival.
Main Methods:
- Assessing intracellular calcium (Ca 2+) responses to ATP stimulation in non-tumorigenic and metastatic breast cancer cells.
- Observing actin polymerization and cell edge localization following ATP activation.
- Utilizing a P2Y2 antagonist to study its effects on Ca 2+ and actin dynamics.
- Correlating P2Y2 expression levels with patient survival data.
Main Results:
- Non-tumorigenic breast epithelial cells show increased intracellular Ca 2+ and actin polymerization upon ATP stimulation via P2Y2 receptor.
- Metastatic breast cancer cells exhibit significantly reduced Ca 2+ responses and lack actin mobilization.
- P2Y2 receptor antagonism in non-tumorigenic cells blunts Ca 2+ increase, prevents actin mobilization, and promotes cell dissemination.
- Reduced P2Y2 expression in metastatic cells correlates with decreased Ca 2+ signaling and poorer patient survival.
Conclusions:
- P2Y2 receptor signaling is critical for normal breast epithelial cell responses to extracellular ATP.
- Metastatic breast cancer cells adapt to evade ATP-induced Ca 2+ signaling and actin mobilization.
- Downregulation of P2Y2 receptor expression in metastatic cancer contributes to disease progression and reduced survival.
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