Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Biol Chem. 2010 Mar 12;285(11):8218-26. doi: 10.1074/jbc.M110.100792. Epub 2010 Jan 6.
The molecular mechanisms governing breast tumor cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and stem cell function. The excision of c-jun by Cre recombinase reduced cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (stem cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor cell invasion and self-renewal.
调控乳腺肿瘤细胞自我更新的分子机制促进了乳腺癌的进展和治疗耐药性。ErbB2 癌基因在大约 30%的人类乳腺癌中过表达。c-Jun 是第一个细胞原癌基因，在人类乳腺癌中过表达。然而，内源性 c-Jun 在乳腺肿瘤进展中的作用尚不清楚。在此，我们将乳腺组织特异性表达 ErbB2 癌基因的转基因小鼠与 c-jun(f/f) 转基因小鼠杂交，以确定内源性 c-Jun 在乳腺肿瘤侵袭和干细胞功能中的作用。Cre 重组酶的切除减少了 ErbB2 诱导的乳腺肿瘤的细胞迁移、侵袭和类器官形成。蛋白质组学分析鉴定出一组由 ErbB2 表达诱导的分泌蛋白（干细胞因子 (SCF) 和 CCL5），这些蛋白依赖于内源性 c-Jun 的表达。SCF 和 CCL5 被鉴定为 c-Jun 转录诱导。CCL5 挽救了 c-Jun 缺陷型乳腺肿瘤细胞侵袭表型。SCF 挽救了 c-Jun 缺陷型乳腺肿瘤细胞类器官生成。因此，内源性 c-Jun 有助于 ErbB2 诱导的乳腺肿瘤细胞侵袭和自我更新。
