Acetylation of α-tubulin and its Role in Aggressive and Metastatic Breast Cancer

Abstract

Metastatic breast cancer presents a therapeutic challenge, since existing treatments largely target primary tumor growth instead of metastatic spread. Because metastasis is the leading cause of breast cancer-related death, we must investigate new targets for the treatment of disseminated disease. This study describes a novel role for α-tubulin acetylation in metastatic breast cancer. We report that metastatic breast cancer cells have high α-tubulin acetylation that is maintained under suspended conditions and extends along microtentacles, tubulin-based protrusions that promote cell-cell and cell-substrate reattachment. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this post-translational modification has a significant impact on microtentacle frequency and suspended tumor cell reattachment. Reducing α-tubulin acetylation in metastatic breast tumor cell lines also significantly inhibits migration, but does not affect proliferation. Investigating the translational importance of this modification in over 140 breast cancer patients' matched primary and metastatic tumors, we find that α-tubulin acetylation is maintained and in many cases increased in nodal metastases, relative to the primary tumor. We also discover a strong correlation between α-tubulin acetylation and the aggressive basal-like breast cancer subtype in a large cohort of breast cancer patients. These data suggest α-tubulin acetylation may promote a more metastatic phenotype through its effects on reattachment and migration while serving as a marker of an aggressive breast cancer subtype.