Characterization of novel transcriptional regulators of aromatase

Aromatase belongs to the cytochrome P450 protein superfamily (encoded by the CYP19A1 gene) and is the key enzyme responsible for estrogen production by converting androgens to estrogens, which in turn promotes tumour growth in estrogen-dependent breast cancers. The expression sites of aromatase exhibit tissue-specific behaviour under the control of various hormonal factors involved in the transcriptional regulation via alternative promoters. In addition, factors such as age and body weight also play a role in the expression of aromatase. For example, aromatase expression in healthy breast pre-adipocytes, also known as adipose fibroblasts in the adipose tissue of menopausal women, is controlled by promoter I.4, which leads to the local estrogen synthesis. As a result, breast tumours preferentially settle in the quadrants with the highest aromatase expression. Glucocorticoids stimulate a well-characterized signalling pathway that leads to aromatase expression via PI.4. In addition, it is assumed that retinoids, which are found in adipose tissue, also control the expression of PI.4, which still needs to be characterized in more detail. The research group led by Dr. Martin Schmidt has studied the effects of retinoids in both mouse 3T3-L1 preadipocytes and human breast adipose fibroblasts (BAFs). They found that PI.4-associated aromatase activity is induced by ligands of retinoic acid receptors including all-trans RA and 9-cis RA. However, promoters I.3/II, which are also used in adipose tissue, do not respond to retinoid-dependent stimulation, demonstrating the specificity of the PI.4 response to retinoid stimulation. Furthermore, activities of different fragments of PI.4 with different lengths showed that retinoid-dependent induction of aromatase by PI.4 relies on a 467 bp fragment (-256/+211 relative to the aromatase PI.4 transcription start site). This region contains four putative retinoic acid response elements (RAREs) that serve as binding-sites for transcription.