Regulation of breast cancer-associated aromatase promoters

Dong Chen*, Scott Reierstad, Meiling Lu, Zhihong Lin, Hiroshi Ishikawa, Serdar E Bulun

*Corresponding author for this work

Research output: Contribution to journalShort survey

53 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15-27
Number of pages13
JournalCancer Letters
Volume273
Issue number1
DOIs
StatePublished - Jan 8 2009

Fingerprint

Aromatase
Breast Neoplasms
Estrogens
Aromatase Inhibitors
Breast
Adipose Tissue
Fibroblasts
Cytokines
Bone and Bones
Breast Diseases
Androstenedione
Estrone
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Epigenomics
Nanoparticles
Placenta
Small Interfering RNA

Keywords

  • Aromatase
  • Breast cancer
  • Estrogen
  • Promoter
  • Transcription

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chen, Dong ; Reierstad, Scott ; Lu, Meiling ; Lin, Zhihong ; Ishikawa, Hiroshi ; Bulun, Serdar E. / Regulation of breast cancer-associated aromatase promoters. In: Cancer Letters. 2009 ; Vol. 273, No. 1. pp. 15-27.
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abstract = "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.",
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Chen, D, Reierstad, S, Lu, M, Lin, Z, Ishikawa, H & Bulun, SE 2009, 'Regulation of breast cancer-associated aromatase promoters', Cancer Letters, vol. 273, no. 1, pp. 15-27. https://doi.org/10.1016/j.canlet.2008.05.038

Regulation of breast cancer-associated aromatase promoters. / Chen, Dong; Reierstad, Scott; Lu, Meiling; Lin, Zhihong; Ishikawa, Hiroshi; Bulun, Serdar E.

In: Cancer Letters, Vol. 273, No. 1, 08.01.2009, p. 15-27.

Research output: Contribution to journalShort survey

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AU - Chen, Dong

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AB - 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.

KW - Aromatase

KW - Breast cancer

KW - Estrogen

KW - Promoter

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