Dysregulated
miRNA expression has been associated with the development and progression of
cancers, including
breast cancer. The role of
estrogen (E2) in regulation of cell proliferation and breast
carcinogenesis is well-known. Recent reports have associated several
miRNAs with
estrogen receptors in breast
cancers. Investigation of the regulatory role of
miRNAs is critical for understanding the effect of E2 in human
breast cancer, as well as developing strategies for
cancer chemoprevention. In the present study we used the well-established ACI rat model that develops mammary
tumors upon E2 exposure and identified a 'signature' of 33 significantly modulated
miRNAs during the process of mammary
tumorigenesis. Several of these
miRNAs were altered as early as 3 weeks after initial E2 treatment and their modulation persisted throughout the mammary
carcinogenesis process, suggesting that these molecular changes are early events. Furthermore,
ellagic acid, which inhibited E2-induced mammary
tumorigenesis in our previous study, reversed the dysregulation of miR-375, miR-206, miR-182, miR-122, miR-127 and miR-183 detected with E2 treatment and modulated their target
proteins (ERĪ±,
cyclin D1, RASD1, FoxO3a, FoxO1,
cyclin G1, Bcl-w and Bcl-2). This is the first systematic study examining the changes in
miRNA expression associated with E2 treatment in ACI rats as early as 3 week until
tumor time point. The effect of a chemopreventive agent,
ellagic acid in reversing
miRNAs modulated during E2-mediated mammary
tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemopreventive action of
ellagic acid and treatment of
breast cancer.