Jeong Joseph H, Wang Zhenxiong, Guimaraes Alexander S, Ouyang Xuesong, Figueiredo Jose L, Ding Zhihu, Jiang Shan, Guney Isil, Kang Gyeong Hoon, Shin Eyoung, Hahn William C, Loda Massimo F, Abate-Shen Cory, Weissleder Ralph, Chin Lynda
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2008;3(12):e3949. doi: 10.1371/journal.pone.0003949. Epub 2008 Dec 16.
Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.
前列腺癌是男性癌症相关死亡的第二大主要原因。尽管缺乏正式的遗传学证据，但丝裂原活化蛋白激酶（MAP）信号通路的激活与晚期及雄激素非依赖性前列腺癌有关。在酪氨酸酶启动子转基因系统中对恶性黑色素瘤进行建模的过程中，我们开发了一种侵袭性前列腺癌的基因工程小鼠（GEM）模型，在Ink4a/Arf基因缺失的背景下，将BRAF（V600E）激活突变（约10%的人类前列腺肿瘤中发现的一种突变）靶向前列腺上皮细胞。这些GEM小鼠出现前列腺增生，并进展为快速生长的侵袭性腺癌，且无AKT激活迹象，这提供了遗传学证据，表明MAP激酶信号通路的激活足以驱动前列腺肿瘤发生。重要的是，在已形成的前列腺肿瘤中BRAF（V600E）基因的消除并未导致肿瘤消退，这表明BRAF（V600E）虽然足以启动侵袭性前列腺腺癌的发生，但并非其维持所必需。
