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BRMS1 Sensitizes Breast Cancer Cells to ATP-Induced Growth Suppression
Yue Zhang1, Karis Chin-Quee, Ryan C Riddle
1Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine , Hershey, Pennsylvania.
Abstract:
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 P2Y2, as well as decreased ATP-induced cytosolic calcium mobilization, relative to hTERT-HME1. However, expressing BRMS1 in MDA-MB-435 cells restored P2Y2 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 P2Y2 receptor.
Insights
Extracellular ATP inhibits breast cancer cell growth, but metastatic cells show resistance. The metastasis suppressor gene BRMS1 enhances sensitivity to ATP by increasing P2Y2 receptor expression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Purinergic signaling, involving extracellular nucleotides like ATP, plays a role in cancer cell growth.
- Altered expression of purinergic receptors is observed in various cancers, making them potential therapeutic targets.
- The metastasis suppressor gene BRMS1 is investigated for its role in modulating cancer cell responses.
Purpose of the Study:
- To investigate the effect of extracellular ATP on the proliferation and apoptosis of metastatic breast carcinoma cells (MDA-MB-435) compared to normal breast epithelial cells (hTERT-HME1).
- To determine if the metastasis suppressor gene BRMS1 influences the sensitivity of breast cancer cells to ATP.
- To elucidate the mechanisms underlying ATP resistance and BRMS1-mediated sensitization.
Main Methods:
- Exposure of MDA-MB-435 and hTERT-HME1 cell lines to varying concentrations and durations of extracellular ATP.
- Assessment of cell proliferation and apoptosis rates.
- Analysis of P2Y2 purinergic receptor expression and ATP-induced cytosolic calcium mobilization.
- Investigation of BRMS1 expression in MDA-MB-435 cells and its impact on ATP sensitivity.
Main Results:
- ATP inhibited proliferation and induced apoptosis in hTERT-HME1 cells within 24 hours.
- MDA-MB-435 cells exhibited resistance to ATP's antiproliferative and apoptosis-inducing effects, requiring higher doses and longer exposure times.
- BRMS1 expression in MDA-MB-435 cells restored sensitivity to ATP's antiproliferative effects and normalized P2Y2 receptor levels and calcium signaling.
Conclusions:
- Metastatic breast cancer cells (MDA-MB-435) display resistance to extracellular ATP compared to normal breast epithelial cells.
- The metastasis suppressor gene BRMS1 enhances the antiproliferative response of breast cancer cells to ATP.
- BRMS1-mediated sensitization to ATP is, at least partly, due to increased expression of the P2Y2 receptor and restored calcium signaling.
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