Aromatase expression and regulation in breast and endometrial cancer

1. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 1

   The estrogen biosynthetic pathway involving the conversion of the substrate cholesterol to progestogens, androgens and finally estrogens. The conversion of androgen to estrone (E1) and estradiol (E2) catalyzed by aromatase (P450arom) is the last and key step for production of estrogen, which binds to estrogen receptor (ER). STAR, steroidogenic acute regulatory protein; P450scc, cholesterol side-chain cleavage enzyme; P450c17, steroid 17α-hydroxylase/17,20 lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase.
2. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 2

   (A) Human aromatase (CYP19A1) and (B) mouse aromatase (Cyp19a1) genes. Expression of the aromatase gene is regulated by the tissue-specific activation of a number of promoters via alternative splicing. Aromatase mRNA species contain promoter-specific 5′-UTRs. The coding region and encoded protein, however, are identical regardless of the promoter used.
3. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 3

   Estrogen synthesis and aromatase promoter II use in the ovary. (A) Gonadotropins (FSH and LH) from the pituitary induce estrogen production in ovary. Progesterone is synthesized from cholesterol via the steroidogenic acute regulatory protein (STAR), the cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD) in both theca and granulosa cells and is converted to androstenedione via steroid 17α-hydroxylase/17, 20 lyase (P450c17) only in theca cells. Theca cell androstenedione is transported into granulosa cells, where it is converted to estrogen by aromatase (P450arom) and 17β-hydroxysteroid dehydrogenase (17β-HSD). (B) FSH induces aromatase expression via a PKA/cAMP-dependent pathway in ovarian granulosa cells via promoter II. SF-1 mediates this action of FSH.
4. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 4

   Alternative promoter use for aromatase expression in normal and malignant breast tissues. Normal breast adipose tissue maintains low levels of aromatase expression primarily via promoter I.4. Promoters I.3 and II are used only minimally in normal breast adipose tissue, whereas promoter I.3 and II activity in breast cancer are strikingly increased. Additionally, the endothelial-type promoter I.7 is upregulated in breast cancer. Thus, the levels of total aromatase mRNA levels from four promoters (II, I.3, I.7 and I.4) in breast cancer tissue are strikingly higher than normal breast tissue.
5. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 5

   Activation of aromatase promoter I.4 and promoters I.3/II in breast adipose fibroblasts and promoter I.7 in breast endothelial cells. (A) Glucocorticoid plus serum stimulates aromatase promoter I.4. Serum can be substituted with TNFα or one of the type I cytokines. Glucocorticoid is obligatory for promoter I.4 stimulation by binding to and activating the glucocorticoid receptor (GR), which interacts with the glucocorticoid response element (GRE) in promoter I.4. TNFα plus glucocorticoid induces expression of c-Jun and c-Fos, which heterodimerize and bind to the AP1 site in promoter I.4. Type I cytokines plus glucocorticoid, on the other hand, activate the JAK1/STAT3 pathway, resulting in binding of tyrosine phosphorylated STAT3 to the interferonγactivation site (GAS) in promoter I.4. Sp1 protein binding to its binding site is also essential for promoter I.4 stimulation. (B) Promoter I.7 is a TATA-less promoter that directs expression of 29–54% of aromatase mRNA species in breast cancer. The −299/−35 regulatory region confers maximum basal activity in endothelial cells and contains at least three critical endothelial-type motifs, including Ets, GATA and E47. The binding of GATA2 protein to the −196/−191 bp site is important for baseline promoter activity in endothelial cells. (C) Breast cancer-conditioned medium and PGE2 can activate aromatase PI.3/II via the activation and binding of various transcription factors to their cis-acting elements, driven by distinct signaling pathways. This is accompanied by binding of LRH-1, CREB1, phosphorylated ATF-2 and c-Jun, JunB, JunD, and C/EBPβ to the promoter I.3/II regulatory region.

• © 2016 Society for Endocrinology