Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1

L. V. Rhodes, C. R. Tate, V. T. Hoang, H. E. Burks, D. Gilliam, E. C. Martin, S. Elliott, D. B. Miller, A. Buechlein, D. Rusch, H. Tang, Kenneth Nephew, M. E. Burow, B. M. Collins-Burow

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere168
JournalOncogenesis
Volume4
DOIs
StatePublished - Oct 5 2015
Externally publishedYes

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Triple Negative Breast Neoplasms
Phosphotransferases
Neoplasm Metastasis
Liver
Breast Neoplasms
Neoplasms
Epithelial-Mesenchymal Transition
RNA Sequence Analysis
Matrix Metalloproteinase 1
Protein-Serine-Threonine Kinases
Vimentin
Heterografts
Cell Adhesion
Extracellular Matrix
Epithelial Cells
Phenotype
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Rhodes, L. V., Tate, C. R., Hoang, V. T., Burks, H. E., Gilliam, D., Martin, E. C., ... Collins-Burow, B. M. (2015). Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1. Oncogenesis, 4, [e168]. https://doi.org/10.1038/oncsis.2015.27

Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1. / Rhodes, L. V.; Tate, C. R.; Hoang, V. T.; Burks, H. E.; Gilliam, D.; Martin, E. C.; Elliott, S.; Miller, D. B.; Buechlein, A.; Rusch, D.; Tang, H.; Nephew, Kenneth; Burow, M. E.; Collins-Burow, B. M.

In: Oncogenesis, Vol. 4, e168, 05.10.2015.

Research output: Contribution to journalArticle

Rhodes, LV, Tate, CR, Hoang, VT, Burks, HE, Gilliam, D, Martin, EC, Elliott, S, Miller, DB, Buechlein, A, Rusch, D, Tang, H, Nephew, K, Burow, ME & Collins-Burow, BM 2015, 'Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1', Oncogenesis, vol. 4, e168. https://doi.org/10.1038/oncsis.2015.27
Rhodes, L. V. ; Tate, C. R. ; Hoang, V. T. ; Burks, H. E. ; Gilliam, D. ; Martin, E. C. ; Elliott, S. ; Miller, D. B. ; Buechlein, A. ; Rusch, D. ; Tang, H. ; Nephew, Kenneth ; Burow, M. E. ; Collins-Burow, B. M. / Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1. In: Oncogenesis. 2015 ; Vol. 4.
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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.",
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