title: Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy.
abstract: Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Alvarez
authors.forename: Tien-Chi
authors.initials: TC
authors.lastname: Pan
authors.forename: Jason
authors.initials: J
authors.lastname: Ruth
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.forename: Alice
authors.initials: A
authors.lastname: Zhou
authors.forename: Dhruv
authors.initials: D
authors.lastname: Pant
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Grimley
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wandless
authors.forename: Angela
authors.initials: A
authors.lastname: Demichele
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D024722:Cardiac Myosins / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000209:etiology*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D024722:Cardiac Myosins; D064550:Death-Associated Protein Kinases; D018994:Myosin Light Chains; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C107184:myosin light chain 2; C101296:prostate apoptosis response-4 protein; C508053:ERBB2 protein, human