Aromatase expression and regulation in breast and endometrial cancer

Abstract

Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to their cis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.

Testosterone Represses Estrogen Signaling by Upregulating miR-22

“…27 The positive feedback of E 2 /ERα signaling is vital to the formation of predominant follicles in the ovary. 34 It was reported that miR-22 was present in the ovary. 35,36 It is most likely that the interaction mechanism between androgen and estrogen also works in the ovary, just as what we found in the placenta.…”

“…The membranes were blocked with 5% non-fat milk or 30 1% BSA in TBS-T (20 mM Tris-HCl, pH 7.4, 150 mM NaCl, and 0.1% Tween-20) and 31 incubated with the appropriate antibodies, following by the corresponding horseradish 32 peroxidase (HRP)-conjugated secondary antibody (Promega, Madison, WI). The signals were 33 visualized using an ECL kit (Thermo Scientific, MA, USA), followed by exposure to X-ray 34 film (Kodak, NY, USA) and analysis using Quantity One ® 1-DAnalysis Software, version 4.4 35 (Bio-Rad, CA, USA). The relative density of each specific molecule was measured by 36 densitometry, and its value was compared with the GAPDH or -actin value from the same blot.…”

The role of estrogens in the adipose tissue milieu

“…71,72 These promoter regions drive aromatase expression in the ovaries and bone, adipose, placental, and neuronal tissue. Human CYP19A1 has at least eight different transcriptional start sites encoding unique upstream exons, each of which is specific to a different tissue.…”

Medical Management of Endometriosis

“…First, the endometrial implants have intrinsic aromatase activity, which leads to the conversion of cholesterol to estradiol. 12 The endometrium is rich in PG-E2 receptors and activation of the PG receptor subtype EP-2 leads to activation of cyclic AMP, which increases the expression of key steroidogenic genes, and aromatase activity eventually leading to increased estradiol production. Along with intrinsic aromatase activity estradiol produced from ovary and peripheral fat also reaches the sites of endometriosis.…”