Expression of estrogen responsive genes in breast cancers correlates with plasma estradiol levels in postmenopausal women.

Abstract

Abstract Abstract #63 Background: Estrogen exposure is linked to the development and treatment of the majority of breast cancers. High estradiol (E2) levels are associated with elevated breast cancer risk in postmenopausal women and estrogen antagonism or withdrawal reduces tumor cell proliferation of ER+ breast cancers. Within postmenopausal breast tumors, E2 concentrations are 10-20 times higher than in plasma. Intratumoral synthesis is thought to be the principal cause of this gradient and consequently to dominate estrogen signaling in postmenopausal breast cancers. Contrary to this expectation, we have made the novel observation that intratumoral expression of estrogen responsive genes is correlated with plasma E2 levels in two independent datasets.
 Methods: Pre- and 2wk post-treatment core-cut tumor biopsies were obtained from 104 postmenopausal women with stage I to IIIB ER+ early breast cancer who received single agent neoadjuvant anastrozole1. RNA extracted from biopsies was analysed on Illumina 48K microarrays. Plasma E2 levels were determined by a highly-sensitive RIA before and after the 2wks treatment. Quantitative trait analysis (QTA) by Spearman correlation was used to identify genes whose expression in pre-treatment tumors or changes upon treatment were significantly correlated with pre-treatment plasma E2 levels. Gene set enrichment analysis (GSEA) was performed on the ranked list of correlated genes. Validation was performed in an independent set of 73 ER+ or PR+ breast cancers.
 Results: QTA revealed that genes whose expression is known to be highly responsive to estrogen were quantitatively associated with plasma E2 levels. For example, TFF1/pS2, GREB1, PDZK1 and PGR were positively correlated with plasma E2 (p<0.001). More generally, gene sets found by GSEA to be associated with the transcriptional response to estrogen deprivation in this sample set, and other published datasets1,2, were also significantly associated with plasma E2. In addition, pre-treatment E2 levels predicted the magnitude of decrease in estrogen responsive genes on treatment.Validation of a subset of E2 regulated genes in the independent tumour set revealed that these were again positively correlated with plasma E2 levels.
 Conclusions: This study shows for the first time that circulating E2 levels are significantly associated with the expression of estrogen responsive genes within ER+ tumors and suggests that intratumoral estrogen synthesis may not be the predominant influence on estrogen signaling in postmenopausal breast tumors. This observation may provide insight into the mechanisms through which elevated plasma E2 levels are associated with breast tumor development and progression. Baseline E2 levels are associated with the biological response to aromatase inhibitor treatment and as a result might influence clinical response.
 1. Stossi et al., Endocrinology, 2004, 145, 3473-86.
 2. Frasor et al., Cancer Res., 2006, 66, 7334-40.
 Supported by The Mary-Jean Mitchell Green Foundation Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 63.