Haynes, B. P., Straume, A. H., Geisler, J., A'Hern, R., Helle, H., Smith, I. E., Lonning, P. E., Dowsett, M. (2010) Intratumoral Estrogen Disposition in Breast Cancer. CLINICAL CANCER RESEARCH, 16 (6). pp. 1790-1801. ISSN 1078-0432

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Abstract

Purpose: The concentration of estradiol (E-2) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E-2 synthesis versus uptake of E-2 from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E-2 levels in breast cancer patients. Experimental Design: The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed. Results: ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER+ tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E-2 levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER+ patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = -0.46, P = 0.0057) and HSD17B12 (r = -0.45, P = 0.0076) showed significant negative correlations with intratumoral E-2 in all patients. Intratumoral E-2 revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E-2 predicted between 50% and 70% of intratumoral E-2 variability. Conclusion: Uptake due to binding to the ER, rather than intratumoral estrogen synthesis by aromatase or sulfatase, is the single most important correlate and a probable determinant of intratumoral E-2. An increased expression of HSD17B7 may explain the increased ratio of E-2 to estrone (E-1) in breast tumors compared with normal tissue. Clin Cancer Res; 16(6); 1790-801. (C) 2010 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Ahern, Roger and Smith, Ian and Dowsett, Mitch
All Authors:	Haynes, B. P., Straume, A. H., Geisler, J., A'Hern, R., Helle, H., Smith, I. E., Lonning, P. E., Dowsett, M.
Uncontrolled Keywords:	17-BETA-HYDROXYSTEROID DEHYDROGENASE; CLINICOPATHOLOGICAL PARAMETERS; AROMATASE INHIBITORS; METABOLIZING ENZYMES; ADIPOSE-TISSUE; EXPRESSION; ESTRADIOL; SULFATASE; THERAPY; ANASTROZOLE
Funding Acknowledgement:	Breast Cancer Research Foundation ; Norwegian Cancer Society ; ``Rosa sloyfe'' Breast Cancer Fund Raising ; Norwegian Health Region West (HelseVest) ; Innovest program of Excellence ; Royal Marsden National Institute for Health Research Biomedical Research Centre
Funding Text:	The Breast Cancer Research Foundation (I. E. Smith and M. Dowsett); the Norwegian Cancer Society, the ``Rosa sloyfe'' Breast Cancer Fund Raising, the Norwegian Health Region West (HelseVest), and the Innovest program of Excellence (all P. E. Lonning); and National Health Service funding to the Royal Marsden National Institute for Health Research Biomedical Research Centre (M. Dowsett).
Research teams:	Clinical Units > Breast Unit ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Users 10 not found.
Date Deposited:	25 Jun 2010 09:22
Last Modified:	21 Jan 2014 16:42
URI:	http://publications.icr.ac.uk/id/eprint/9684

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