title: LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dupuy
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Physiology, McGill University, McIntyre Building, Room 705, Montréal, Québec 3655, Canada.
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Physiology, McGill University, McIntyre Building, Room 705, Montréal, Québec 3655, Canada.
authors.forename: Julianna
authors.initials: J
authors.lastname: Blagih
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors.forename: Gäelle
authors.initials: G
authors.lastname: Bridon
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Room 513, 1160 Pine Avenue, West, Montréal, Québec, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Doris R
authors.initials: DR
authors.lastname: Siwak
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Room 513, 1160 Pine Avenue, West, Montréal, Québec, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Room 513, 1160 Pine Avenue, West, Montréal, Québec, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Physiology, McGill University, McIntyre Building, Room 705, Montréal, Québec 3655, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones