期刊
CANCER RESEARCH
卷 82, 期 20, 页码 -出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-0698
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类别
资金
- NIH-NCI [P30 CA054174]
- NIH Shared Instrument grant [1S10OD021805-01]
- CPRIT Core Facility Award [RP160732, RP160844]
- [VA-1 101 BX004545-01]
- [NIH-CA239227]
- [NIH F31-CA257298]
- [CPRIT RP160844]
A novel peptide inhibitor called SMIP34 has been found to efficiently inhibit the oncogenic signaling of PELP1, a coregulator implicated in therapy-resistant ER+ breast cancer. SMIP34 blocks the interaction between PELP1 and its target, reduces cell growth, induces PELP1 degradation, and alters gene expression related to estrogen response, cell cycle, and apoptosis pathways.
Most patients with estrogen receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line-derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer. Significance: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.
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