Abstract
BackgroundGermline 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.MethodsWe 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.ResultsWe 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.ConclusionsTogether, 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.
Highlights
Germline and somatic mutations in Serine threonine kinase 11 (STK11), the gene encoding the serine/threonine kinase Liver kinase B1 (LKB1), are strongly associated with tumorigenesis
Reduced LKB1 expression in breast cancer cells promotes an invasive phenotype To characterize the effect of LKB1 loss on tumor cell phenotype further, we investigated the status of cell polarity in Human epidermal growth factor receptor 2 (ErbB2)-positive breast cancer cells with reduced LKB1 expression
While loss of LKB1 expression has previously been linked to breast cancer, the exact role of LKB1 in regulating breast cancer development and metabolism has remained unclear
Summary
Germline and somatic mutations in STK11, the gene encoding the serine/threonine kinase LKB1, are strongly associated with tumorigenesis. The STK11 gene encodes the protein kinase LKB1, a serine threonine kinase that plays a multi-faceted role in cell biology [7]. Given its diversity of kinase targets, LKB1 has been characterized as a ‘master’ kinase that regulates diverse cellular processes, including cell polarity, energy metabolism, apoptosis, and cell proliferation [7,13,14,15]. All of these processes play a role in cancer initiation and progression, and may contribute at some level to the tumor suppressor effects of LKB1
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