Department of Pathology, Breast Cancer Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Oncogene. 2009 Dec 17;28(50):4491-500. doi: 10.1038/onc.2009.297. Epub 2009 Sep 28.
Earlier, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.
早些时候，我们在食管癌细胞系中对 9p23-24 扩增子进行了作图，导致我们对鳞状细胞癌 1 中基因扩增（GASC1）进行了定位克隆，该基因编码一种具有 Jumonji C 结构域的核蛋白，该结构域可催化组蛋白赖氨酸（K）去甲基化。然而，GASC1 在乳腺癌中的转化作用仍有待确定。在这项研究中，我们确定 GASC1 是乳腺癌 9p23-24 区域扩增基因之一，特别是在基底样亚型中。与非基底样乳腺癌相比，GASC1 转录物表达水平在侵袭性、基底样乳腺癌中显著升高。我们的体外实验表明，当在永生化、非转化的乳腺上皮 MCF10A 细胞中过表达时，GASC1 可诱导转化表型，包括生长因子非依赖性增殖、无锚定生长、Matrigel 中形态发生改变和乳腺球形成能力。此外，GASC1 去甲基酶活性调节包括 NOTCH1 在内的对干细胞自我更新至关重要的基因的表达，并且可能与乳腺癌中的干细胞表型有关。因此，GASC1 是人类乳腺癌 9p23-24 扩增子中的驱动癌基因，针对 GASC1 组蛋白去甲基酶的靶向抑制可能为癌症治疗开发提供新的途径。
