Summary

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.

Significance

Recurrent breast cancer is typically an incurable disease. Consequently, the propensity of breast cancers to recur following surgery, radiation, and adjuvant therapy is the most important determinant of clinical outcome. Residual neoplastic cells that persist following treatment constitute the reservoir from which recurrent tumors arise and are a major obstacle to the successful treatment of human cancers. Accordingly, understanding the mechanisms by which residual tumor cells survive treatment is a critical research priority. Our findings establish downregulation of the tumor suppressor Par-4 in mice and in women as a mechanism of tumor cell survival and recurrence following targeted therapy and chemotherapy. As such, therapies that target pathways repressed by Par-4—or that restore Par-4 expression—may hold significant clinical promise.