title: 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.
authors.affiliation: Division of Reproductive Science in MedicineDepartment of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA h-zhao@northwestern.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Reproductive Science in MedicineDepartment of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Reproductive Science in MedicineDepartment of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Anna Junjie
authors.initials: AJ
authors.lastname: Shangguan
authors.affiliation: Division of Reproductive Science in MedicineDepartment of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004967:Estrogens; D014157:Transcription Factors; D001141:Aromatase
keywords: aromatase; breast cancer; endometrial cancer; estrogen