Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.
Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.
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DOI：
10.1007/s10549-016-3807-y
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发表时间：
2016-05
影响因子：
3.8
通讯作者：
Ince TA
中科院分区：
文献类型：
--
作者：
Thakkar A;Wang B;Picon-Ruiz M;Buchwald P;Ince TA
抗雌激素和抗 HER2 治疗是乳腺癌 (BC) 靶向治疗的最早也是最成功的例子之一。然而，缺乏雌激素受体表达或 HER2 扩增的三阴性乳腺癌 (TNBC) 的治疗仍然是一个重大挑战。我们之前发现，大约三分之二的 TNBC 表达维生素 D 受体 (VDR) 和/或雄激素受体 (AR)，并假设共表达 AR 和 VDR 的 TNBC (HR2-av TNBC) 可以通过靶向这两种激素受体来治疗。为了评估 VDR/AR 靶向治疗在 TNBC 中的可行性，我们对 15 个不同的 BC 系进行了表征，并鉴定了 2 个 HR2-av TNBC 系，并检查了 VDR 和 AR 靶向治疗后它们的表型、活力和增殖的变化。用 VDR 或 AR 激动剂处理 BC 细胞系会以受体依赖性方式抑制细胞活力，并且它们的组合似乎会叠加抑制细胞活力。此外，当AR/VDR激动激素与化疗药物联合使用时，细胞活力进一步下降。 AR/VDR激动激素的抑制机制包括TNBC细胞系中的细胞周期停滞和细胞凋亡。此外，AR/VDR 激动剂激素诱导分化并抑制癌症干细胞 (CSC)，具体表现为肿瘤球形成效率的降低、醛脱氢酶的高活性和 CSC 标记物的降低。令人惊讶的是，我们发现 AR 拮抗剂以不依赖于 AR 的方式抑制大多数 BC 细胞系的增殖，这引发了对其作用机制的疑问。综上所述，AR/VDR靶向激动激素治疗能够以受体依赖性方式通过多种机制抑制HR2-av TNBC，并且可以与化疗联合使用。本文的在线版本 (doi:10.1007/s10549-016-3807-y) 包含补充材料，可供授权用户使用。
Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy. The online version of this article (doi:10.1007/s10549-016-3807-y) contains supplementary material, which is available to authorized users.