AbstractTPD52 and ERBB2 co‐expression has been persistently reported in human breast cancer and animal models of this disease, but the significance of this is unknown. We identified significant positive associations between relativeTPD52andERBB2transcript levels in human diagnostic breast cancer samples, and maximalTPD52expression in the hormone receptor (HR)‐ and ERBB2‐positive sub‐group. High‐levelTPD52expression was associated with significantly reduced metastasis‐free survival, within the overall cohort (log rank test,P = 8.6 × 10−4,n = 375) where this was an independent predictor of metastasis‐free survival (hazard ratio, 2.69, 95% confidence interval 1.59–4.54,P = 2.2 × 10−4,n = 359), and the HR‐ and ERBB2‐positive sub‐group (log rank test,P = 0.035,n = 47). Transient TPD52 knock‐down in theERBB2‐amplified breast cancer cell lines SK‐BR‐3 and BT‐474 produced significant apoptosis, both singly and in combination with transient ERBB2 knock‐down. Unlike ERBB2 knock‐down, transient TPD52 knock‐down produced no reduction in pAKT levels in SK‐BR‐3 or BT‐474 cells. We then derived multiple SK‐BR‐3 cell lines in which TPD52 levels were stably reduced, and measured significant inverse correlations between pERBB2 and TPD52 levels in viable TPD52‐depleted and control cell lines, all of which showed similar proliferative capacities. Our results therefore identify TPD52 as a survival factor inERBB2‐amplified breast cancer cells, and suggest complementary cellular functions for TPD52 and ERBB2. © 2013 Wiley Periodicals, Inc.