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Background  High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol.    Methods  We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations.    Results  Six genes ( SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1 ) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as  SCGB3A1  ( HIN1 ) and  TLN2  were up-regulated and  PTGS1  ( COX1 ) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of  GREB1  and  AREG  was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases.    Conclusions  We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas.  SCGB3A1  is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans.

Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas