Aromatase, breast cancer and obesity: a complex interaction

Abstract

Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE(2) production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit.

Figure 1

Structure of the CYP19A1 gene. The human CYP19A1 (aromatase) gene is transcribed in the direction from the telomere towards the centromere of chromosome 15 and contains approximately 10 alternatively used native promoters that regulate its expression in a partially tissue-specific fashion. Activation of each promoter transcribes on mRNA species that contains a specific 5′-untranslated region (5′-UTR), which serves as the signature of that particular promoter. Five other genes (TLN2, CGNL1, MAPK6, TMOD3 and DMXL2) clustered in tandem order lie next to aromatase at its telomeric aspect. Heterozygous inversions or deletions change the direction of these genes’ promoters and their 5′-UTRs and move them upstream of the aromatase gene. These cryptic promoters then inappropriately overexpress aromatase in multiple human tissues and cause estrogen excess. The most common manifestation is the feminine growth of breast tissue in young boys (prepubertal gynecomastia) (see [40] for further details).

Figure 2

Stromal–epithelial interactions for estrogen production in breast cancer. Breast cancer grows in an environment of adipose tissue. Adipose fibroblasts differentiate to mature adipocytes in the breast. Both cell types lie in close proximity to benign or malignant epithelial cells. The products of malignant and benign cells determine the key biological features of this micro-environment. For example, malignant cells and adipose fibroblasts secrete PGE₂ that induces aromatase (CYP19A1) expression in undifferentiated adipose fibroblasts. Aromatase converts androstenedione to estrone, that is further converted to biologically active estradiol, by 17β- hydroxysteroid dehydrogenase type 1 (HSD17B1) in the same cell or in the malignant epithelial cell. Alternatively, the enzyme aldo–keto reductase family 1, member C3 (AKR1C3), which is expressed in myofibroblasts of breast tissue, converts androstenedione to testosterone that may be readily aromatized to estradiol. Thus, PGE₂ induces estradiol production directly or indirectly via regulating aromatase enzyme activity in adipose fibroblasts. Once an adipose fibroblast is differentiated into a mature adipocyte it loses its capacity to express aromatase and form estradiol. Malignant breast epithelial cells secrete antiadipogenic cytokines such as TNF and IL-11 to inhibit this differentiation. It appears that malignant epithelial cells maintain neighboring adipose cells in an undifferentiated state to maximize paracrine estradiol biosynthesis.

Figure 3

Signaling pathways for estrogen production and action. PGE₂ that originates from malignant epithelial cells or adipose fibroblasts activates specific signaling mechanisms to induce aromatase expression in adipose fibroblasts. The best characterized and most potent components of the PGE₂-dependent signaling pathway in the adipose fibroblast are PKA/PKC and p38/JNK. Some of the key transcription factors downstream of this pathway include C/EBPβ, JunD and JunB, and LRH-1 which bind to the tumorigenic aromatase promoter region I.3/II (see text). The key cis-regulatory elements, C/EBPβ-S and CRE and the promoters II and I.3, cluster within a sequence of less than 300 bp. LRH-1 binds to a nuclear receptor half-site located more proximal to promoter II (PII). It is very likely that these key elements regulate the activity of both promoters coordinately. The details of this complex regulation are not well understood. Estrogen produced as a consequence of aromatase activity acts on estrogen receptor-α (ERα) in neighboring epithelial cells to enhance carcinogenesis by transactivating specific genes. PKA, protein kinase A; PKC, protein kinase C; C/EBP, CCAAT/enhancer binding protein; C/EBPβ-S, C/EBPβ site; CRE, cAMP response element; PR, progesterone receptor, Wnt, wingless-type MMTV integration-site family; ADORA, adenosine A1 receptor.