Loss of lkb1 Expression Reduces the Latency of ErbB2-Mediated Mammary Gland Tumorigenesis, Promoting Changes in Metabolic Pathways

Andrade-Vieira, Rafaela; Xu, Zhaolin; Colp, Patricia; Marignani, Paola A.
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
The tumor suppressor kinase LKB1 is mutated in a broad range of cancers however, the role of LKB1 mammary gland tumorigenesis is not fully understood. Evaluation of human breast cancer tissue microarrays, indicate that 31% of HER2 positive samples lacked LKB1 expression. To expand on these observations, we crossed STK11fl/fl mice with mice genetically engineered to express activated Neu/HER2-MMTV-Cre (NIC) under the endogenous Erbb2 promoter, to generate STK11−/−/NIC mice. In these mice, the loss of lkb1 expression reduced the latency of ErbB2-mediated tumorigenesis compared to the latency of tumorigenesis in NIC mice alone. Analysis of STK11−/−/NIC mammary tumors revealed hyperactivation of mammalian target of rapamycin (mTOR) through both mTORC1 and mTORC2 pathways as determined by the phosphorylation status of ribosomal protein S6 and AKT. Furthermore, STK11−/−/NIC mammary tumors had elevated ATP levels along with changes in metabolic enzymes and metabolites. The treatment of primary mammary tumor cells with specific mTOR inhibitors AZD8055 and Torin1, that target both mTOR complexes, attenuated mTOR activity and decreased expression of glycolytic enzymes. Our findings underscore the existence of a molecular interplay between LKB1-AMPK-mTORC1 and ErbB2-AKT-mTORC2 pathways with mTOR at its epicenter, suggestive that loss of LKB1 expression may serve as a marker for hyperactivated mTOR in HER2 positive breast cancer and warranting further investigation into therapeutics that target LKB1-AMPK-mTOR and glycolytic pathways.


Related Articles

  • Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis. Wu, L; de Bruin, A; Wang, H; Simmons, T; Cleghorn, W; Goldenberg, L E; Sites, E; Sandy, A; Trimboli, A; Fernandez, S A; Eng, C; Shapiro, C; Leone, G // Oncogene;1/2/2015, Vol. 34 Issue 1, p119 

    Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains...

  • Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. Bing Zhou; Damrauer, Jeffrey S.; Bailey, Sean T.; Hadzic, Tanja; Youngtae Jeong; Clark, Kelly; Cheng Fan; Murphy, Laura; Lee, Cleo Y.; Troester, Melissa A.; Miller, C. Ryan; Jian Jin; Darr, David; Perou, Charles M.; Levine, Ross L.; Diehn, Maximilian; Kim, William Y. // Journal of Clinical Investigation;Feb2014, Vol. 124 Issue 2, p553 

    Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased...

  • LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway. Zhuang, Zhigang; Wang, Kai; Cheng, Xiaolin; Qu, Xueying; Jiang, Beiqi; Li, Zhengdong; Luo, Jianming; Shao, Zhiming; Duan, Tao // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation...

  • miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. Gebeshuber, C A; Martinez, J // Oncogene;7/4/2013, Vol. 32 Issue 27, p3306 

    Dysregulation of micro RNAs is crucially implicated in tumorigenesis. We detected downregulation of miR-100 in breast cancer cells, leading to an upregulation of the proliferation- and survival-promoting oncogene insulin-like growth factor (IGF) 2. Stable overexpression of miR-100 strongly...

  • YAP Promotes Ovarian Cancer Cell Tumorigenesis and Is Indicative of a Poor Prognosis for Ovarian Cancer Patients. Xia, Yan; Chang, Ting; Wang, Yingmei; Liu, Yixiong; Li, Wenhui; Li, Ming; Fan, Heng-Yu // PLoS ONE;Mar2014, Vol. 9 Issue 3, p1 

    YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we...

  • Gpr177 Deficiency Impairs Mammary Development and Prohibits Wnt-Induced Tumorigenesis. Maruyama, Eri Ohfuchi; Yu, H-M. Ivy; Jiang, Ming; Fu, Jiang; Hsu, Wei // PLoS ONE;Feb2013, Vol. 8 Issue 2, p1 

    Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties...

  • Deep Sequencing Reveals New Aspects of Progesterone Receptor Signaling in Breast Cancer Cells. Kougioumtzi, Anastasia; Tsaparas, Panayiotis; Magklara, Angeliki // PLoS ONE;Jun2014, Vol. 9 Issue 6, p1 

    Despite the pleiotropic effects of the progesterone receptor in breast cancer, the molecular mechanisms in play remain largely unknown. To gain a global view of the PR-orchestrated networks, we used next-generation sequencing to determine the progestin-regulated transcriptome in T47D breast...

  • IQGAP3 Promotes EGFR-ERK Signaling and the Growth and Metastasis of Lung Cancer Cells. Yang, Ying; Zhao, Wei; Xu, Qing-Wen; Wang, Xiao-Song; Zhang, Yu; Zhang, Jun // PLoS ONE;May2014, Vol. 9 Issue 5, p1 

    Proteins of the IQGAP family display complicated and often contradictory activities in tumorigenesis. IQGAP1 has well documented oncogenic potential and IQGAP2 has putative tumor-suppressive function. IQGAP3 is the latest addition to this family and its role in cancer development remains to be...

  • p120 catenin is a key effector of a Ras-PKCÉ› oncogenic signaling axis. Dann, S G; Golas, J; Miranda, M; Shi, C; Wu, J; Jin, G; Rosfjord, E; Upeslacis, E; Klippel, A // Oncogene;3/13/2014, Vol. 33 Issue 11, p1385 

    Within the family of protein kinase C (PKC) molecules, the novel isoform PRKCE (PKCÉ›) acts as a bona fide oncogene in in vitro and in vivo models of tumorigenesis. Previous studies have reported expression of PKCÉ› in breast, prostate and lung tumors above that of normal adjacent tissue....


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics