Abstract
Women outlive men, but life expectancy is not influenced by hormone replacement (estrogen + progestin) therapy. Estrogens appear to protect brain, cardiovascular tissues, and bone from aging. Estrogens regulate genes directly through binding to estrogen receptors alpha and beta (ERα and ERβ) that are ligand-activated transcription factors and indirectly by activating plasma membrane-associated ER which, in turns, activates intracellular signaling cascades leading to altered gene expression. MicroRNAs (miRNAs) are short (19-25 nucleotides), naturally-occurring, non-coding RNA molecules that base-pair with the 3’ untranslated region of target mRNAs. This interaction either blocks translation of the mRNA or targets the mRNA transcript to be degraded. The human genome contains ~ 700-1,200 miRNAs. Aberrant patterns of miRNA expression are implicated in human diseases including breast cancer. Recent studies have identified miRNAs regulated by estrogens in human breast cancer cells, human endometrial stromal and myometrial smooth muscle cells, rat mammary gland, and mouse uterus. The decline of estradiol levels in postmenopausal women has been implicated in various age-associated disorders. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in aging has yet to be explored.
Highlights
Animal studies have shown that higher estrogen levels in females protect against aging by upregulating the expression of antioxidant, longevity-related genes, e.g., selenium-dependent glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD) [1], by protecting against stroke-related injury [2], by vasorelaxing effects [3], by direct myocardial protection [4], and by activating the insulin receptor substrate (IRS)-1 signaling pathway [5]
We demonstrated that miR-21 binds to a seed element in the 3'-UTR of the programmed cell death 4 (PDCD4) gene and reduces Pdcd4 protein expression [193]
There are a number of studies identifying miRNA changes in breast tumors and comparing ERpositive versus estrogen receptor (ER)-negative miRNA signatures for their potential use as biomarkers, there are few studies identifying E2-responsive miRNAs in any normal or neoplastic tissues or cell models
Summary
In addition to direct ER-ERE binding, ER activates transcription via a “tethering mechanism” in which ER interacts directly with transcription factors, e.g. Sp1 [41] and AP-1 [42], bound to their response elements These DNA-protein and protein-protein interactions recruit coactivator/chromatin remodeling complexes resulting in histone modifications that lead to nucleosomal remodeling, increased accessibility to the DNA template for RNA polymerase II interaction, and increased target gene transcription (reviewed in [43,44,45]). A recent study reported that miR-21 expression was reduced in breast tumors and that antisense to miR-21 suppressed MCF-7 breast cancer cell growth in vitro and as tumor xenografts in mice by regulating Bcl-2 [13].
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