Post-translational regulation of aromatase in aging

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.