Post-translational regulation of aromatase in aging

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Summary: Alterations in estrogen signaling contribute to a spectrum of abnormalities ranging from skeletal dysplasias to Alzheimer’s disease (AD) that impact both physiology and behavior. The CYP19A1 gene encodes aromatase which is the final enzyme in the estrogen biosynthesis pathway that converts androgens to estrogens. Synthesis of estrogen throughout the body can be regulated spatially and temporally depending on the tissue. The impact of estrogen extends beyond stimulation of ER and ER and has recently been shown to regulate the function of G- protein coupled estrogen receptors in diverse tissues. Moreover, the impact of 17-estradiol (E2) on stromal and immune cells is important in the regulation of the immune system and dysfunctional signaling has been linked with auto-immune diseases. Despite the critically important role of aromatase in biology in tissues and organs ranging from the epithelial tissue to the brain to bones, many major knowledge gaps remain regarding the regulation of aromatase at the transcriptional and post-translational level. Recently, our lab made two major discoveries. First, our recent reports were the first to establish that Dishevelled proteins, key regulators of Wnt signaling, bind to multiple CYP19A1 tissue specific promoters and modulate aromatase expression. These recent observations could provide significant insight into mechanisms of aging-related pathologies. Recent reports establish links between CYP19A1 gene alterations and AD and show altered neuroendocrinology and steroidogenesis in women with AD. Animal models further show the importance of aromatase dysregulation in aging related pathologies. Second, our group was the first to identify novel post-translational modification (PTM) regulatory lysines that control aromatase enzyme activity. Prior to our report, nothing was known about the extent to which lysine acetylation modulates aromatase activity. We hypothesize that aromatase PTMs will be influenced by aging in vivo. We now demonstrate that aromatase PTMs modulate aromatase inhibitor sensitivity and proposed studies are significant because they will be the first to dissect newly identified post-translational mechanisms of aromatase control as a function of aging in mammary gland tissue as a function of age using different transgenic mouse models. We will also identify novel aromatase PTMs in mammary gland tissue as a function of age via LC- MS/MS acetylation mapping. These studies represent an exciting new angle since virtually nothing is known about the role of aromatase PTMs in vivo in mammary gland tissue in general, and in particular, as a function of age. We further hypothesize that there are novel aromatase PTMs that are characteristic of the age-linked mammary gland microenvironments.