BRMS1 Sensitizes Breast Cancer Cells to ATP-Induced Growth Suppression

Purinergic signaling may represent an effective target in cancer therapy because the expression of purinergic receptors is altered in many forms of cancer and extracellular nucleotides modulate cancer cell growth. We examined the effect of extracellular ATP on the growth of the metastatic breast carcinoma cell line MDA-MB-435 relative to an immortalized breast epithelial cell line, hTERT-HME1. We also investigated whether the metastasis suppressor gene BRMS1 alters the sensitivity of breast cancer cells to ATP. Exposure to ATP for 24 h decreased proliferation and induced apoptosis in hTERT-HME1. However, exposure to ATP did not decrease proliferation or induce apoptosis in MDA-MD-435 cells until 48 h of exposure and only at higher doses than were effective with hTERT-HME1, suggesting MDA-MB-435 cells were resistant to the antiproliferative and apoptosis-inducing effects of ATP. Exposure to ATP for 24 h induced a decrease in proliferation of MDA-MB-435 cells expressing BRMS1, similar to hTERT-HME1, but did not induce an increase in apoptosis. MDA-MB-435 cells expressed low levels of the purinergic receptor P2Y(2), as well as decreased ATP-induced cytosolic calcium mobilization, relative to hTERT-HME1. However, expressing BRMS1 in MDA-MB-435 cells restored P2Y(2) levels and ATP-induced cytosolic calcium mobilization such that they were similar to hTERT-HME1. These data suggest that BRMS1 increases the sensitivity of breast cancer cells to the antiproliferative, but not apoptosis-inducing effects of ATP and that this is at least partly mediated by increased expression of the P2Y(2) receptor.