MicroRNA ‘signature’ during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention

Abstract

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 for 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 (ERα, 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 was also established. These observations provide mechanistic insights into the new molecular events behind the chemoprevention action of ellagic acid in and treatment of breast cancer.

MiR-203 inhibits estrogen-induced viability, migration and invasion of estrogen receptor α-positive breast cancer cells

“…In the present study, it was demonstrated that treatment with E2 significantly enhanced the viability, migration and invasion of ERα-positive breast cancer cells. Previously, Munagala et al used the August-Copenhagen Irish rat model, which develops mammary tumors by E2 treatment, to investigate changes in miRs during the process of mammary tumorigenesis, and found that several miRs, such as miR-375, -206, -182, -122, -127 and -183, were dysregulated throughout the mammary carcinogenesis process (24). These findings suggest that certain miRs are involved in the development of breast cancer.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…[302] p57, Bax and caspase-3 miR-206 is a potent tumor supressor p57 and Bax upregulated, and cleaved caspase-3 protein upregulated ACI model rat mammary tissue [308] Actin-like 6A (BAF53a), a subunit of the SWI/SNF chromatin remodeling complex Elevated BAF53a Downregulation of miR-206 Primary rhabdomyosarcoma tumors [309] Actin-like 6A (BAF53a) BAF53a transcript is significantly higher in primary rhabdomyosarcomas than in normal muscle…”

miR-148a Suppresses estrogen-induced viability and migration of breast cancer cells via inhibition of estrogen receptor α expression

“…Furthermore, treatment with E2 has previously been found to cause deregulation of many miRs during the mammary carcinogenesis process (30), suggesting that miRs may play a role in breast cancer. For instance, miR-125b was found to be significantly upregulated in breast cancer, and its upregulation was associated with poor prognosis and aromatase inhibitor resistance (31).…”