c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression.
We previously reported that constitutive c-Abl activity (CST-Abl) abrogates the tumorigenicity of triple-negative breast cancer cells through the combined actions of two cellular events: downregulated matrix metalloproteinase (MMP) and upregulated p21Waf1/Cip1 expression. We now find decreased c-Abl expression to be significantly associated with diminished relapse-fee survival in breast cancer patients, particularly those exhibiting invasive and basal phenotypes. Moreover, CST-Abl expression enabled 4T1 cells to persist innocuously in the mammary glands of mice, doing so by exhausting their supply of cancer stem cells. Restoring MMP-9 expression and activity in CST-Abl-expressing 4T1 cells failed to rescue their malignant phenotypes; however, rendering these same cells deficient in p21 expression not only delayed their acquisition of senescent phenotypes, but also partially restored their tumorigenicity in mice. Although 4T1 cells lacked detectable expression of p53, those engineered to express CST-Abl exhibited robust production and secretion of TGF-β1 that engendered the reactivated expression of p53. Mechanistically, TGF-β-mediated p53 expression transpired through the combined actions of Smad1/5/8 and Smad2, leading to the dramatic upregulation of p21 and its stimulation of TNBC senescence. Collectively, we identified a novel c-Abl:p53:p21 signaling axis that functions as a powerful suppressor of mammary tumorigenesis and metastatic progression.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Chevaun D
CD
Morrison
Department of Pharmacology, Anschutz Medical Campus, University of Colorado-Denver, Aurora, CO 80045, USA.
Tressa M
TM
Allington
Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
Cheryl L
CL
Thompson
Department of Pathology, University Hospitals, Case Medical Center and Case Western Reserve University, Cleveland, OH 44106, USA.
Hannah L
HL
Gilmore
Houston Methodist Research Center, Houston, TX 77030, USA.
Jenny C
JC
Chang
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
Ruth A
RA
Keri
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
William P
WP
Schiemann
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics* / Q000378:metabolism; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D016315:Proto-Oncogene Proteins c-abl; D020780:Matrix Metalloproteinase 9
breast cancer; c-Abl; p53; transforming growth factor-β; triple-negative breast cancer