Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
BMC Cancer. 2011 Aug 3;11:332. doi: 10.1186/1471-2407-11-332.
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.
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.
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.
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.
血清雌二醇水平升高与绝经后乳腺癌风险增加有关。关于循环血清雌二醇水平与正常乳腺组织基因表达的关系知之甚少。
我们比较了 79 名健康女性和 64 名乳腺癌患者的乳腺组织样本和血清激素水平的全基因组表达数据。使用差异表达基因的微阵列分析（SAM）和多元线性回归分析来识别独立关联。
根据血清雌二醇水平，发现 6 个基因（SCGB3A1、RSPO1、TLN2、SLITRK4、DCLK1、PTGS1）表达差异（FDR = 0）。这 6 个基因中有 3 个在多变量模型中独立预测雌二醇水平，即高血清雌二醇水平的女性乳腺组织中 SCGB3A1（HIN1）和 TLN2 上调，PTGS1（COX1）下调。血清雌二醇与多谱勒密度（另一个强烈的乳腺癌危险因素）无显著相关性，而这些差异表达基因也无显著相关性。在乳腺癌中，GREB1 和 AREG 的表达与所有癌症以及雌激素受体阳性病例亚组的血清雌二醇相关。
我们已经确定了与正常乳腺组织和乳腺癌中血清雌二醇水平相关的基因。SCGB3A1 是一种可能的肿瘤抑制基因，可抑制细胞生长和侵袭，在许多上皮性癌症中被甲基化和下调。我们的研究结果表明，在高雌二醇水平的健康女性中，该基因是一种重要的乳腺细胞增殖抑制剂。在乳腺中，该基因仅在腔细胞中表达，在非 BRCA 相关乳腺癌中被甲基化。进一步探讨该基因失活对腔细胞而非基底样癌致癌作用的可能性是必要的。PTGS1 诱导前列腺素 E2（PGE2）的产生，进而刺激芳香化酶的表达，从而增加局部雌二醇的产生。这是首次在人类正常乳腺组织中研究这种关联的报告。
