title: α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.
abstract: Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of α-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high α-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this posttranslational modification exerted a significant impact on McTN frequency and the reattachment of suspended tumor cells. Reducing α-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of more than 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared with primary tumors. Proteomic analysis of an independent cohort of more than 390 patient specimens further documented the relationship between increased α-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high-intensity α-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated α-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in patients with breast cancer.
authors.affiliation: University of Maryland, Baltimore, Graduate Program in Life Sciences, Baltimore, Maryland. University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Boggs
authors.affiliation: University of Maryland, Baltimore, Graduate Program in Life Sciences, Baltimore, Maryland. University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Michele I
authors.initials: MI
authors.lastname: Vitolo
authors.affiliation: University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Whipple
authors.affiliation: University of Maryland, Baltimore, Graduate Program in Life Sciences, Baltimore, Maryland. University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Charpentier
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Goloubeva
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Ioffe
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Tuttle
authors.affiliation: University of Maryland, Baltimore, Graduate Program in Life Sciences, Baltimore, Maryland. University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland.
authors.forename: Jana
authors.initials: J
authors.lastname: Slovic
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: University of Maryland, Baltimore, Graduate Program in Life Sciences, Baltimore, Maryland. University of Maryland Marlene and Stewart Greenebaum NCI Cancer Center, Baltimore, Maryland. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland. ssmartin@som.umaryland.edu.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Martin
mesh_terms: D000107:Acetylation; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D016019:Survival Analysis; D014404:Tubulin / Q000378:metabolism*
chemical_list: D014404:Tubulin