Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Republic of Singapore.
Oncol Rep. 2018 Nov;40(5):2525-2535. doi: 10.3892/or.2018.6676. Epub 2018 Aug 31.
A majority of breast cancer cases are positive for the estrogen receptor (ER), which means that they can respond to the estrogen hormone to achieve growth. Hence, the ER signaling pathway has been extensively targeted in pharmaceutical research and development in order to suppress tumor growth. However, prevalent hormone therapy and targeted therapy often become ineffective as cancer cells ultimately develop resistance, suggesting that there could be unidentified signaling molecules and events that regulate breast cancer growth. Notably, recent studies have uncovered that Piwi‑like (Piwil) proteins, which were initially found in germline cells, are expressed in a wide spectrum of human cancers, including breast cancers. Although Piwil proteins have been well established to silence retrotransposons and to promote heterochromatin formation in germline cells, their somatic functions in cancer cells remain largely unknown. In the present study, we profiled the expression of four Piwi homologs in an ER‑positive breast cancer cell line, MCF‑7, and found that only Piwil4 was upregulated by 17β‑estradiol treatment. Notably, Piwil4 upregulation was not observed in an ER‑positive but non‑tumorigenic breast cancer cell line, MCF‑12A. In addition, the induced expression of Piwil4 was dependent on estrogen/ERα signaling. To explore the biological significance of Piwil4 in breast cancer growth, we knocked down Piwil4 with multiple siRNAs and observed the suppressed expression of some canonical targets of ER. The knockdown of Piwil4 expression also decreased the migration and invasion capabilities of MCF‑7 cells. Furthermore, the loss‑of‑function of Piwil4 reduced the motility of MCF‑7 cells in wound‑healing assays, which could be associated to decreased expression of vimentin and N‑cadherin. Collectively, these findings revealed that Piwil4 is a novel regulator of ER signaling that could be targeted to inhibit breast cancer growth and migration.
大多数乳腺癌病例的雌激素受体（ER）呈阳性，这意味着它们可以对雌激素激素做出反应以实现生长。因此，ER 信号通路已在药物研发中得到广泛研究，以抑制肿瘤生长。然而，由于癌细胞最终产生抗药性，常用的激素疗法和靶向疗法往往变得无效，这表明可能存在调节乳腺癌生长的未识别信号分子和事件。值得注意的是，最近的研究发现，最初在生殖细胞中发现的 Piwi 样（Piwil）蛋白在广泛的人类癌症中表达，包括乳腺癌。尽管 Piwil 蛋白已被很好地确立为沉默逆转录转座子并促进生殖细胞中的异染色质形成，但它们在癌细胞中的体细胞功能仍知之甚少。在本研究中，我们对 ER 阳性乳腺癌细胞系 MCF-7 中的四种 Piwi 同源物的表达进行了分析，发现只有 Piwil4 被 17β-雌二醇处理上调。值得注意的是，在 ER 阳性但非致瘤性乳腺癌细胞系 MCF-12A 中未观察到 Piwil4 的上调。此外，Piwil4 的诱导表达依赖于雌激素/ERα 信号。为了探讨 Piwil4 在乳腺癌生长中的生物学意义，我们使用多种 siRNA 敲低 Piwil4，并观察到 ER 的一些典型靶标表达受到抑制。Piwil4 表达的敲低也降低了 MCF-7 细胞的迁移和侵袭能力。此外，Piwil4 的功能丧失会降低 MCF-7 细胞在划痕愈合测定中的运动能力，这可能与波形蛋白和 N-钙黏蛋白表达的降低有关。总之，这些发现表明 Piwil4 是 ER 信号的新型调节因子，可作为抑制乳腺癌生长和迁移的靶点。
