Par-4 Down-regulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy

Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-...

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Bibliographic Details
Published inCancer cell Vol. 24; no. 1
Main Authors Alvarez, James V., Pan, Tien-chi, Ruth, Jason, Feng, Yi, Zhou, Alice, Pant, Dhruv, Grimley, Joshua S., Wandless, Thomas J., DeMichele, Angela, Chodosh, Lewis A.
Format Journal Article
LanguageEnglish
Published 13.06.2013
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Summary:Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation 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 breast cancer patients, and Par-4 is down-regulated 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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.05.007