Transcriptional control of local estrogen formation by aromatase in the breast.
Aromatase is the critical enzyme that converts androgens to estrogens. It is frequently highly expressed in the tumour bearing breast of women diagnosed with estrogen receptor positive tumours, resulting in dramatically increased local estrogen production to drive tumour progression. Expression of aromatase is regulated primarily at the transcriptional level of its encoding gene CYP19A1, located on chromosome 15 of the human genome. A characteristic feature of CYP19A1 expression is its use of alternative promoters to regulate transcription in a tissue-specific manner. In breast cancer, the increase in aromatase expression is mediated via higher expression of the distal adipose-specific promoter I.4 and a switch to the preferential use of proximal promoters I.3 and II. This results in a net increase of CYP19A1 transcripts in tumour-bearing breast up to 3-4-fold higher than normal breast. Current aromatase inhibitors - whilst efficacious - exhibit significant side effects that reduce patient compliance. Understanding the transcription factors and signalling pathways that control aromatase expression will lead to opportunities to develop breast-specific inhibitors with an improved side-effects profile. This article is part of a Special Issue entitled 'Essential role of DHEA'.
Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia. Electronic address: sarah.to@princehenrys.org.
Sarah Q
SQ
To
Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia. Electronic address: kevin.knower@princehenrys.org.
Kevin C
KC
Knower
Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
Vanessa
V
Cheung
Metabolism and Cancer Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
Evan R
ER
Simpson
Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
Colin D
CD
Clyne
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000378:metabolism*; D014158:Transcription, Genetic
D004967:Estrogens; D011960:Receptors, Estrogen; D001141:Aromatase; C561410:CYP19A1 protein, human
Aromatase; Aromatase inhibitors; Breast cancer; Estrogen