Most patients with estrogen receptor alpha–positive (ERþ) breast SMIP34 inhibited proliferation of not only wild-type (WT) but also cancers initially respond to treatment but eventually develop mutant (MT) ERþ and therapy-resistant breast cancer cells, in part therapy resistance with disease progression. Overexpression of by inducing PELP1 degradation via the proteasome pathway. RNA oncogenic ER coregulators, including proline, glutamic acid, and sequencing analyses showed that SMIP34 treatment altered the leucine-rich protein 1 (PELP1), are implicated in breast cancer expression of genes associated with estrogen response, cell cycle, progression. The lack of small molecules that inhibits PELP1 and apoptosis pathways. In cell line–derived and patient-derived represents a major knowledge gap. Here, using a yeast-two-xenografts of both WT and MT ERþ breast cancer models, hybrid screen, we identified novel peptide inhibitors of PELP1 SMIP34 reduced proliferation and significantly suppressed tumor (PIP). Biochemical assays demonstrated that one of these peptides, progression. Collectively, these results demonstrate SMIP34 as a PIP1, directly interacted with PELP1 to block PELP1 oncogenic first-in-class inhibitor of oncogenic PELP1 signaling in advanced functions. Computational modeling of PIP1 revealed key residues breast cancer. contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses Significance: Development of a novel inhibitor of oncogenic confirmed that SMIP34 directly bound to PELP1. In breast cancer PELP1 provides potential therapeutic avenues for treating therapy-cells, SMIP34 reduced cell growth in a dose-dependent manner. resistant, advanced ERþ breast cancer.
ASJC Scopus subject areas
- Cancer Research