title: Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1.
abstract: Liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), has been identified as a tumor suppressor in many cancers including breast. Low LKB1 expression has been associated with poor prognosis of breast cancer patients, and we report here a significant association between loss of LKB1 expression and reduced patient survival specifically in the basal subtype of breast cancer. Owing to the aggressive nature of the basal subtype as evidenced by high incidences of metastasis, the purpose of this study was to determine if LKB1 expression could regulate the invasive and metastatic properties of this specific breast cancer subtype. Induction of LKB1 expression in basal-like breast cancer (BLBC)/triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, inhibited invasiveness in vitro and lung metastatic burden in an orthotopic xenograft model. Further analysis of BLBC cells overexpressing LKB1 by unbiased whole transcriptomics (RNA-sequencing) revealed striking regulation of metastasis-associated pathways, including cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT). In addition, LKB1 overexpression inhibited EMT-associated genes (CDH2, Vimentin, Twist) and induced the epithelial cell marker CDH1, indicating reversal of the EMT phenotype in the MDA-MB-231 cells. We further demonstrated marked inhibition of matrix metalloproteinase 1 expression and activity via regulation of c-Jun through inhibition of p38 signaling in LKB1-expressing cells. Taken together, these data support future development of LKB1 inducing therapeutics for the suppression of invasion and metastasis of BLBC.
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Rhodes
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Tate
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: V T
authors.initials: VT
authors.lastname: Hoang
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Burks
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gilliam
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Martin
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Elliott
authors.affiliation: Department of Cellular and Integrative Physiology, Bloomington, IN, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Center for Genomics and Bioinformatics, College of Arts and Sciences, Indiana University School of Medicine and Simon Cancer Center, Bloomington, IN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Buechlein
authors.affiliation: Center for Genomics and Bioinformatics, College of Arts and Sciences, Indiana University School of Medicine and Simon Cancer Center, Bloomington, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Rusch
authors.affiliation: Center for Genomics and Bioinformatics, College of Arts and Sciences, Indiana University School of Medicine and Simon Cancer Center, Bloomington, IN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Cellular and Integrative Physiology, Bloomington, IN, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Nephew
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Burow
authors.affiliation: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Collins-Burow