By converting
androstenedione to
estrone, or
testosterone to
estradiol,
aromatase is a key
enzyme in
estrogen biosynthesis. Encoded by a single gene
CYP19,
aromatase is expressed in various tissues, including ovary, placenta, bone, brain, skin, and adipose tissue, via partially tissue-specific promoters, and is essential for normal
estrogen-dependent physiological functions. In disease-free breast tissue,
aromatase mRNA is primarily transcribed from the weak promoter I.4 and maintained at low levels in breast adipose stromal fibroblasts. In
breast cancer a distinct set of
aromatase promoters, i.e. I.3, II, and I.7, is activated, leading to a marked increase in
aromatase expression in
breast tumors and breast adipose tissue adjacent to a
breast tumor, and a consequent local overproduction of
estrogen that promotes growth and progression of
breast cancer. In addition, the total amount of promoter I.4-specific
aromatase transcript in breast adipose fibroblasts may also be increased due to both
cytokine-induced desmoplastic reaction and
cytokine-stimulated promoter I.4 activity in
breast cancer. Targeting
aromatase has proven beneficial in treating
breast cancer, since
aromatase inhibitors are the most effective endocrine treatment of
breast cancer to date. However,
aromatase inhibitors cause major side effects such as bone loss and abnormal lipid metabolism, due to indiscriminate reduction of
aromatase activity in all expression sites of the body. Therefore, inhibition of
aromatase expression via
breast cancer-associated
aromatase promoters is a useful strategy to selectively block local
aromatase production, and hence
estrogen synthesis, in
breast cancer. This review will summarize the significant findings on regulation of the
breast cancer-associated
aromatase promoters, and highlight the discovery of chemical compounds and
nuclear receptor ligands that specifically inhibit activation of these
aromatase promoters. Clinical side effects of these agents require development of new drugs with better specificity and efficacy, and epigenetic
therapies with
breast cancer tissue-selective
aromatase siRNA-conjugated nanoparticles.