Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Obstetrics and Gynecology, The Third Xiangya Hospital, Central South University, Changsha, China; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Lett. 2019 Oct 1;461:21-30. doi: 10.1016/j.canlet.2019.06.011. Epub 2019 Jun 20.
Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC). To identify potential genetic drivers of ILC progression, we used NanoString nCounter technology to investigate the DNA copy number (CN) in 70 well-curated primary ILC samples. We confirmed prior observations of frequent amplification of CCND1 (33%), and MYC (17%) in ILC, but additionally identified a substantial subset of ILCs with ESR1 and ERBB2 (19%) amplifications. Of interest, tumors with ESR1 CN gains (14%) and amplification (10%) were more likely to recur compared to those with normal CN. Finally, we observed that MDM4 (MDMX) was amplified in 17% of ILC samples. MDM4 knockdown in TP53 wild-type ILC cell lines caused increased apoptosis, decreased proliferation associated with cell cycle arrest, and concomitant activation of TP53 target genes. Similar effects were seen in TP53 mutant cells, indicting a TP53-independent role for MDM4 in ILC. To conclude, amplification of ESR1 and MDM4 are potential genetic drivers of ILC. These amplifications may represent actionable, targetable tumor dependencies, and thus have potential clinical implications and warrant further study.
浸润性小叶癌（ILC）是继浸润性导管癌（IDC）之后第二常见的乳腺癌组织学亚型。为了鉴定 ILC 进展的潜在遗传驱动因素，我们使用 NanoString nCounter 技术检测了 70 个精心挑选的原发性 ILC 样本中的 DNA 拷贝数（CN）。我们证实了先前在 ILC 中 CCND1（33%）和 MYC（17%）频繁扩增的观察结果，但另外还鉴定出具有 ESR1 和 ERBB2（19%）扩增的相当一部分 ILC。有趣的是，与具有正常 CN 的肿瘤相比，具有 ESR1 CN 增益（14%）和扩增（10%）的肿瘤更有可能复发。最后，我们观察到 17%的 ILC 样本中存在 MDM4（MDMX）扩增。在 TP53 野生型 ILC 细胞系中敲低 MDM4 会导致细胞凋亡增加、增殖减少与细胞周期停滞相关，并且同时激活 TP53 靶基因。在 TP53 突变细胞中也观察到类似的效果，表明 MDM4 在 ILC 中发挥了 TP53 非依赖性作用。总之，ESR1 和 MDM4 的扩增可能是 ILC 的潜在遗传驱动因素。这些扩增可能代表可操作的、可靶向的肿瘤依赖性，因此具有潜在的临床意义，值得进一步研究。
