Let-7 family miRNAs regulate estrogen receptor alpha signaling in estrogen receptor positive breast cancer.
In order to understand how microRNAs (miRNAs) regulate breast cancer tumorigenesis, a miRNA expression microarray screening was performed using RNA from formalin-fixed paraffin-embedded (FFPE) breast tissues, which included benign (n = 13), ductal carcinoma in situ (DCIS) (n = 16), and invasive ductal carcinoma (IDC) (n = 15). Twenty-five differentially expressed miRNAs (P < 0.01) were identified, of which let-7 family miRNAs were down-regulated in human breast cancer tissues at stages of DCIS and IDC compared to benign stage. We further found that there was an inverse correlation between ER-α expression and several members of let-7 family in the FFPE tissues. Next, we performed bioinformatics analysis and found that let-7 miRNA sequences match sequence in the 3'-UTR of estrogen receptor alpha (ER-α), suggesting ER-α may be a target of let-7, which was further confirmed by a number of experimental assays, including luciferase assay, protein expression, and mRNA expression. Overexpression of let-7 miRNAs in ER-positive breast cancer MCF7 cell line negatively affected ER-α activity. As expected, dampening of the ER-α signaling by let-7 miRNAs inhibited cell proliferation, and subsequently triggered the cell apoptotic process in MCF7 cells. In conclusion, our findings indicate a new regulatory mechanism of let-7 miRNAs in ER-α mediated cellular malignant growth of breast cancer.
Genomics & Functional Proteomics Laboratories, Osteoporosis Research Center, Creighton University Medical Center, 601 N 30th ST, Suite 6730, Omaha, NE 68131, USA.
Yingchun
Y
Zhao
Caishu
C
Deng
Jiarui
J
Wang
Jing
J
Xiao
Zoran
Z
Gatalica
Robert R
RR
Recker
Gary Guishan
GG
Xiao
D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human