Cancer Res：雌激素受体D538G突变诱发乳腺癌耐药

虽然乳腺癌患者最初响应激素疗法如他莫昔芬，但最终会抵抗治疗。近日，一项新的研究发现，乳腺癌患者抵抗治疗可能是因为癌细胞雌激素受体存在一种突变（雌激素受体是他莫昔芬发挥功效所必须结合的受体），相关研究结论发表在Cancer Research杂志上。Ido Wolf说：几乎所有的转移性乳腺癌患者最初回应内分泌激素治疗，但最终发展抵抗这些治疗。我们发现雌激素受体的一种新突变（雌激素受体是内分泌治疗的靶标），突变使受体更活跃，更耐内分泌治疗，更重要的是，我们发现38％患者存在这一突变。

目前对内分泌治疗产生耐药的乳腺癌患者唯一的治疗选择是化疗，与内分泌治疗相比，化疗剧毒，效益也较低。Wolf说：我们发现了一个非常简单明了的耐药机制，通过使用现代测序技术，我们发现了新的突变。

Wolf和他的同事们收集13例原发性乳腺癌和肝脏转移性肿瘤样本。所有患者初期接受内分泌治疗，但终告失败。Wolf团队通过一个复杂的深度测序方法对原发性乳腺癌和转移性肝肿瘤进行了基因组。研究人员偶然发现：在五个样本中，雌激素受体存在突变。

他们发现，这种突变称为D538G，原发性乳腺癌样品中不存在，只存在于肝脏转移性肿瘤样本。由于这种突变，受体的结构发生改变，它无法再结合他莫昔芬。使用实验室培养乳腺癌细胞进一步实验，Wolf和他的同事们发现，由于其结构的变化，受体独立运作，引起癌细胞不受控制增殖，使肿瘤更具侵略性，导致对治疗反应迟钝。

以往研究大多是关注于原发肿瘤，这可能是为什么D538G突变从未被检测到。根据Wolf，描述：我们能检测到D538G突变，是因为我们在正确的时间采样肿瘤。他解释说，我们现在需要找到办法来抑制这种受体突变，发展比化疗更有效，毒性较低的疗法。（转化医学网360zhyx.com）

原文链接：

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D538G Mutation in Estrogen Receptor-α: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity. Cancer Res; 1–9. ?2013 AACR.

来源：bioon