LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer.
LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer.
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DOI：
10.1186/2049-3002-1-18
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发表时间：
2013-08-14
影响因子：
5.9
通讯作者：
Jones RG
中科院分区：
文献类型：
--
作者：
Dupuy F;Griss T;Blagih J;Bridon G;Avizonis D;Ling C;Dong Z;Siwak DR;Annis MG;Mills GB;Muller WJ;Siegel PM;Jones RG
编码丝氨酸/苏氨酸激酶LKB1的基因STK11的种系和体细胞突变与肿瘤的发生密切相关。虽然LKB1的表达缺失与乳腺癌有关，但LKB1在调节乳腺癌的发生、转移和肿瘤代谢中的作用机制尚不清楚。我们已经建立并分析了在LKB1野生型或LKB1缺陷小鼠的乳腺上皮中表达ErbB2的转基因小鼠。我们还利用了表达ErbB2的乳腺癌细胞，在这些细胞中，LKB1水平已经通过shRNA方法降低。这些转基因和异种移植模型的特点是LKB1缺失对肿瘤的起始、生长、转移和肿瘤细胞代谢的影响。我们证明，在ErbB2介导的乳腺癌模型中，LKB1的缺失促进了肿瘤的启动，并诱导了特征的向有氧糖酵解的转变(‘Warburg效应’)。LKB1缺失的乳腺癌细胞在体外表现出促进早期肿瘤生长的作用，并伴随着细胞迁移和侵袭特性的增强。我们发现，缺乏LKB1的ErbB2阳性肿瘤表现出促生长的分子和表型特征，其特征是Akt/mTOR信号增强，糖酵解代谢增强，以及体内和体外生物能标志物的增加。我们还证明了mTOR有助于LKB1缺陷的乳腺癌的代谢重编程，并需要驱动这些肿瘤中的糖酵解代谢；然而，LKB1缺陷的乳腺癌细胞表现出降低的代谢灵活性和增加的细胞凋亡来响应代谢扰动。综上所述，我们的数据表明LKB1在乳腺癌中起着肿瘤抑制因子的作用。LKB1的缺失与激活的ErbB2信号协同作用，推动乳腺肿瘤的发生和由此产生的肿瘤中的促生长代谢。
Germline and somatic mutations in STK11, the gene encoding the serine/threonine kinase LKB1, are strongly associated with tumorigenesis. While loss of LKB1 expression has been linked to breast cancer, the mechanistic role of LKB1 in regulating breast cancer development, metastasis, and tumor metabolism has remained unclear. We have generated and analyzed transgenic mice expressing ErbB2 in the mammary epithelium of LKB1 wild-type or LKB1-deficient mice. We have also utilized ErbB2-expressing breast cancer cells in which LKB1 levels have been reduced using shRNA approaches. These transgenic and xenograft models were characterized for the effects of LKB1 loss on tumor initiation, growth, metastasis and tumor cell metabolism. We demonstrate that loss of LKB1 promotes tumor initiation and induces a characteristic shift to aerobic glycolysis (‘Warburg effect’) in a model of ErbB2-mediated breast cancer. LKB1-deficient breast cancer cells display enhanced early tumor growth coupled with increased cell migratory and invasive properties in vitro. We show that ErbB2-positive tumors deficient for LKB1 display a pro-growth molecular and phenotypic signature characterized by elevated Akt/mTOR signaling, increased glycolytic metabolism, as well as increased bioenergetic markers both in vitro and in vivo. We also demonstrate that mTOR contributes to the metabolic reprogramming of LKB1-deficient breast cancer, and is required to drive glycolytic metabolism in these tumors; however, LKB1-deficient breast cancer cells display reduced metabolic flexibility and increased apoptosis in response to metabolic perturbations. Together, our data suggest that LKB1 functions as a tumor suppressor in breast cancer. Loss of LKB1 collaborates with activated ErbB2 signaling to drive breast tumorigenesis and pro-growth metabolism in the resulting tumors.