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

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... 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. Abbreviations: BMI, body mass index; IHC, immunohistochemistry; PR, progesterone receptor. Haynes et al. NOTE: Significant correlations (P < 0.05) are in boldface; n is the number of data points (for full details, please refer to "Patient demographics"). Haynes et al.