Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Blickagången 6, S-141 83 Huddinge, Sweden.
Breast Cancer Res. 2011 Apr 14;13(2):R43. doi: 10.1186/bcr2865.
The inhibition of estrogen receptor (ER) α action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ERβ in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ERβ can modulate pathways implicated in endocrine resistance development.
T47-D and MCF-7 ERα-expressing breast cancer cells with tetracycline-regulated expression of ERβ were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit.
Expression of ERβ in ERα-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ERβ. Furthermore, ERβ increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ERβ expression increased the sensitivity of these breast cancer cells to tamoxifen.
Our results suggest a link between expression of ERβ and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ERβ presence in breast cancer samples is an indicator for endocrine response. Current therapies in ERα-positive breast cancers aim to impair ERα activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ERβ as a target in selected groups of breast cancer.
用雌激素受体（ER）拮抗剂他莫昔芬抑制 ERα 活性是大多数乳腺癌的标准治疗方法。对这种治疗的新出现或获得性耐药很常见。在乳腺肿瘤中表达 ERβ 被认为是他莫昔芬敏感性的指标。但这一观察结果背后的机制在很大程度上仍未得到充分描述。在本研究中，我们研究了 ERβ 是否可以调节与内分泌耐药发展相关的途径。
使用四环素调控 ERβ 表达的 T47-D 和 MCF-7 ERα 表达的乳腺癌细胞作为模型系统。通过进行定量聚合酶链反应分析、Western blot 分析和免疫染色，分析已知的内分泌抵抗调节剂的表达水平和活性，并使用细胞增殖试剂盒研究他莫昔芬的敏感性。
在 ERα 阳性的 T47-D 和 MCF-7 人乳腺癌细胞中表达 ERβ 导致 Akt 信号转导减少。Akt 的上游调节剂原癌基因 c-ErbB-2/受体酪氨酸激酶 erbB-3（HER2/HER3）受体二聚体的活性形式也被 ERβ 下调。此外，ERβ 增加了 Akt 的重要抑制剂磷酸酶和张力蛋白同源物缺失 10 号染色体（PTEN）的表达。重要的是，ERβ 的表达增加了这些乳腺癌细胞对他莫昔芬的敏感性。
我们的研究结果表明，通过增加 PTEN 水平和降低 HER2/HER3 信号，表达 ERβ 与内分泌敏感性之间存在联系，从而降低 Akt 信号，随后对乳腺癌细胞的增殖、存活和他莫昔芬敏感性产生影响。这项研究支持进一步研究乳腺肿瘤样本中 ERβ 的存在是否是内分泌反应的指标的倡议。目前针对 ERα 阳性乳腺癌的治疗方法旨在通过拮抗剂或用芳香酶抑制剂去除内源性雌激素来损害 ERα 活性。本研究的数据可被视为也将 ERβ 作为某些乳腺癌患者的治疗靶点的指示。
