Breast cancer is a highly heterogeneous disease with distinct histologic subtypes. Targeted therapies such as endocrine therapy and growth factor receptor inhibitors have had a significant impact on the treatment of metastatic breast cancer patients. Unfortunately, resistance to these agents eventually occurs, and currently represents a significant clinical problem in the management of breast cancers. Inhibitors of histone deacetylases (HDACi) exhibit anticancer activity in a variety of tumor cell models and have been shown to target mechanisms of resistance to a number of targeted agents. It is unclear, however, if there are specific breast cancer subtypes for which an HDACi may be more or less effective. Here, we report that the class I isoform-selective HDACi entinostat (SNDX-275) preferentially inhibits cell proliferation/survival and inactivates downstream signaling in erbB2-overexpressing compared with basal breast cancer cells. SNDX-275 reduces the levels of both erbB2 and erbB3, as well as significantly decreases P-erbB2, P-erbB3, P-Akt, and P-MAPK in erbB2-overexpressing cells. Additionally, SNDX-275 promotes apoptosis and induces cell cycle arrest predominantly at G(1) phase in erbB2-overexpressing cells, whereas SNDX-275 mainly induces G(2)-M arrest in basal breast cancer cells. The cellular bias of SNDX-275 is shown to be related partly to the levels of erbB3 expression that directly impact the ability of SNDX-275 to inhibit proliferation/survival of the erbB2-overexpressing breast cancer cells. These findings show that SNDX-275 may be developed as a novel therapeutic agent to treat breast cancers with coexpression of both erbB2 and erbB3.