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Aromatase excess in cancers of breast, endometrium and ovary
Serdar E Bulun1, Dong Chen, Meiling Lu
1Robert H. Lurie Comprehensive Cancer Center and Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA. s-bulun@northwestern.edu
Abstract:
Pathogenesis and growth of three common women's cancers (breast, endometrium and ovary) are linked to estrogen. A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kb regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers of breast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter I.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE(2) via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE(2) secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE(2) may play important roles in inducing local production of estrogen that promotes tumor growth.
Insights
Aromatase inhibitors treat breast cancer, but their role in endometrial and ovarian cancers is unclear. Inflammatory substances like PGE(2) may drive local estrogen production, promoting tumor growth in these cancers.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Estrogen drives the growth of breast, endometrial, and ovarian cancers.
- Aromatase is the key enzyme in estrogen biosynthesis; its inhibitors are used in breast cancer treatment.
- The role of aromatase inhibitors in endometrial and ovarian cancers requires further investigation.
Purpose of the Study:
- To investigate the role of aromatase in endometrial and ovarian cancers.
- To explore the regulatory mechanisms of aromatase expression in these cancers.
- To understand the impact of inflammatory substances on aromatase activity and tumor growth.
Main Methods:
- Analysis of aromatase expression in normal tissues and cancers.
- Identification of tissue-specific promoters and transcription factors regulating aromatase.
- Investigation of signaling pathways, including cAMP-PKA and PKC, in aromatase regulation.
Main Results:
- Breast, endometrial, and ovarian cancers overexpress aromatase, producing local estrogen.
- Aromatase expression is primarily regulated by the promoter I.3/II region in these cancers.
- Prostaglandin E2 (PGE(2)) stimulates aromatase expression via cAMP-PKA and PKC pathways, potentially promoting tumor growth.
Conclusions:
- Local estrogen production driven by aromatase overexpression contributes to the pathogenesis of breast, endometrial, and ovarian cancers.
- Inflammatory mediators like PGE(2) play a significant role in upregulating aromatase in cancer tissues.
- Targeting aromatase and inflammatory pathways may offer therapeutic strategies for these gynecological cancers.
