TY - JOUR
T1 - Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells
AU - Lopez, Veronica
AU - Kelleher, Shannon L.
N1 - Funding Information:
We thank Dr. Liping Huang (Western Human Nutrition Research Center) for the generous gift of anti-Zip6 antibody, Dr. Colin Duckett (University of Michigan Medical School) for the 4×-MRE-luciferase plasmid, Farnaz Foolad for excellent technical support and Dr. Andrea Mastro for critical reading of the manuscript. All confocal microscopy was done at the Cytometry Facility, University Park (Huck Institutes of the Life Sciences, Penn State University). This work was supported by DOD#BC062742 to S.L.K.
PY - 2010/2/1
Y1 - 2010/2/1
N2 - Breast cancer is associated with zinc (Zn) hyper-accumulation in breast tissue which is postulated to be potentiated by the over-expression of Zn importing proteins. Zip6 (LIV-1) over-expression has been documented in estrogen receptor-positive (ER+) breast tumors. Anti-estrogens, such as fulvestrant, are typically prescribed for ER+ breast cancer and thus may play a role in modulating cellular Zn hyper-accumulation. Herein, we investigated the physiological relevance of Zip6 over-expression and the consequences of Zip6-attenuation in breast tumor cells as a mechanism in the development of anti-estrogen resistance. We documented that over-expression of Zip6 was associated with significantly higher cellular Zn levels in tumor cells compared with normal breast cells. Fulvestrant significantly reduced Zn accumulation in tumor cells, without robust effects on Zip6 protein abundance. Zip6-attenuation significantly reduced cellular Zn pools, which was associated with increased mitochondrial membrane potential (ΔΨm) and decreased apoptotic stimuli (cytoplasmic cytochrome C release, caspase- 3 and - 9 activities). Importantly, decreased apoptosis significantly increased tumor colony formation in soft agar and was associated with reduced E-cadherin expression. Our data suggest that anti-estrogen treatment regulates Zn level and importantly verify that Zip6 over-expression is not an underlying mechanism initiating breast cancer, but in fact may play a "tumor-constraining" role.
AB - Breast cancer is associated with zinc (Zn) hyper-accumulation in breast tissue which is postulated to be potentiated by the over-expression of Zn importing proteins. Zip6 (LIV-1) over-expression has been documented in estrogen receptor-positive (ER+) breast tumors. Anti-estrogens, such as fulvestrant, are typically prescribed for ER+ breast cancer and thus may play a role in modulating cellular Zn hyper-accumulation. Herein, we investigated the physiological relevance of Zip6 over-expression and the consequences of Zip6-attenuation in breast tumor cells as a mechanism in the development of anti-estrogen resistance. We documented that over-expression of Zip6 was associated with significantly higher cellular Zn levels in tumor cells compared with normal breast cells. Fulvestrant significantly reduced Zn accumulation in tumor cells, without robust effects on Zip6 protein abundance. Zip6-attenuation significantly reduced cellular Zn pools, which was associated with increased mitochondrial membrane potential (ΔΨm) and decreased apoptotic stimuli (cytoplasmic cytochrome C release, caspase- 3 and - 9 activities). Importantly, decreased apoptosis significantly increased tumor colony formation in soft agar and was associated with reduced E-cadherin expression. Our data suggest that anti-estrogen treatment regulates Zn level and importantly verify that Zip6 over-expression is not an underlying mechanism initiating breast cancer, but in fact may play a "tumor-constraining" role.
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U2 - 10.1016/j.yexcr.2009.10.011
DO - 10.1016/j.yexcr.2009.10.011
M3 - Article
C2 - 19852955
AN - SCOPUS:72149086674
SN - 0014-4827
VL - 316
SP - 366
EP - 375
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 3
ER -