PDEF Promotes Luminal Differentiation and Acts as a Survival Factor for ER-Positive Breast Cancer Cells

• PDEF induces a luminal expression profile in nontransformed mammary epithelial cells
• PDEF contributes to the molecular differences between luminal and basal breast cancer
• PDEF and GATA3 are anticorrelated and strongly predict clinical outcome
• PDEF promotes luminal breast cancer survival and hormone-independent tumor growth

SummaryBreast cancer is a heterogeneous disease and can be classified based on gene expression profiles that reflect distinct epithelial subtypes. We identify prostate-derived ETS factor (PDEF) as a mediator of mammary luminal epithelial lineage-specific gene expression and as a factor required for tumorigenesis in a subset of breast cancers. PDEF levels strongly correlate with estrogen receptor (ER)-positive luminal breast cancer, and PDEF transcription is inversely regulated by ER and GATA3. Furthermore, PDEF is essential for luminal breast cancer cell survival and is required in models of endocrine resistance. These results offer insights into the function of this ETS factor that are clinically relevant and may be of therapeutic value for patients with breast cancer treated with endocrine therapy.