A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer

Abstract

Most patients with estrogen receptor alpha-positive breast cancers (ER+ BC) 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 BC 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 (PIPs). 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 BC cells, SMIP34 reduced cell growth in a PELP1-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant (TR) BC cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA-seq 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+ BC 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 BC.

CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer

“…Targeting coregulators in disease has for many years been seen as attractive due to the potential advantage of altering specific transcriptional programmes while leaving other key signalling nodes intact[ 22 – 26 ]. The potential for future therapeutic targeting of CITED1 is further strengthened by recent developments of co-regulator interference/manipulation by peptides, such as a PELP-derived peptide targeting ERα signalling and a CITED2-derived peptide which interferes with HIF1α/p300 interaction [ 27 , 28 ].…”

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34

“…The effects of SMIP34 treatment on cell viability was assessed by using the MTT cell viability assay in 96-well plates as described [ 14 ]. Colony formation assays were done as described [ 14 ].…”

“…The effects of SMIP34 treatment on cell viability was assessed by using the MTT cell viability assay in 96-well plates as described [ 14 ]. Colony formation assays were done as described [ 14 ]. Briefly, BT-549 and MDA-MB-231 model cell lines (500 cells/well) were seeded in 6-well plates and allowed to grow for 5 days in control or SMIP34 treated medium and then medium was changed to normal medium and allowed to grow for 5–7 more days.…”

“…Previously, a small molecule inhibitor of PELP1 (SMIP34) which displayed a distinct ability to block PELP1 oncogenic signaling was identified and characterized [ 14 ]. In this study, we investigated whether SMIP34 has utility in treating TNBC.…”

Cited1 as a Marker of Favourable Outcome in Anti-endocrine Treated Erα-positive, Lymph Node Negative Breast Cancer

“…Targeting coregulators in disease has for many years been seen as attractive due to the potential advantage of altering speci c transcriptional programmes while leaving other key signalling nodes intact[18] [19][20] [21,22]. The potential for future therapeutic targeting of CITED1 is further strengthened by recent developments of co-regulator interference/manipulation by peptides, such as a PELP-derived peptide targeting ERα signalling and a CITED2-derived peptide which interferes with HIF1α/p300 interaction [23] [24].…”