Year: 2022
Type: article
Abstract: 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.
Source: Cancer Research
Authors: Kristin A. Altwegg, Suryavathi Viswanadhapalli, Monica Mann, Dimple Chakravarty, Samaya Krishnan, Zexuan Liu, Junhao Liu, Uday P. Pratap, Behnam Ebrahimi, John R. Sanchez, Xiaonan Li, Shihong Ma, Ben H. Park, Bindu Santhamma, Yidong Chen, Zhao Lai, Ganesh V. Raj, Yaxia Yuan, Daohong Zhou, Gangadhara R. Sareddy, Rajeshwar R. Tekmal, Stan McHardy, Tim H.-M. Huang, Manjeet K. Rao, Hariprasad Vankayalapati, Ratna K. Vadlamudi
Institutions: The University of Texas at San Antonio Health Science Center, Mays Cancer Center at UT Health San Antonio, Weill Cornell Medicine, Central South University, Xiangya Hospital Central South University, The University of Texas Southwestern Medical Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Evestra (United States), The University of Texas at San Antonio, Huntsman Cancer Institute, Audie L. Murphy Memorial VA Hospital, South Texas Veterans Health Care System
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Awards: G1143455775, G1143696820, FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers, Mays Cancer Center at UT Health SA, Development of Small Molecule Inhibitor of PELP1 for Treating Advanced Breast Cancer, High Throughput DNA Sequencer: Illumina HiSeq 3000 Sequencer, UTHealth-LINK- A PREP program, G4411463291, PELP1, a Novel Regulator of Estrogen Receptor, UTHSCSA Cancer Genome Sequencing and Computation Core, G5746677394, G5827286289, G7190250055, Center for Innovative Drug Discovery: Enhancement of a Shared Cancer Resource for South Texas, miRNAs:Safe and effective therapeutic adjuvants for treating drug resistant TNBC, G8922965079, G9000324485, Advancing Cancer Research Through Next Generation Sequencing at Mays Cancer Center of UT Health San Antonio
OpenAlex ID: W4290804033