Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy.Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy.However,the function of the majority of KMTs in TNBC has remained largely unknown.In the current study,we found that KMT nuclear receptor binding.SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients.NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth.Mechanistically,NSD2 directly controls the expression of EGFR and ADAMg,a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors,such as HB-EGF.Through its methylase activity,NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib.Together,our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.