Dataset Information

Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.

ABSTRACT: The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85? regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85? heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.

SUBMITTER: Lee KM

PROVIDER: S-EPMC7599336 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.

Lee Kyung-Min KM Guerrero-Zotano Angel L AL Servetto Alberto A Sudhan Dhivya R DR Lin Chang-Ching CC Formisano Luigi L Jansen Valerie M VM González-Ericsson Paula P Sanders Melinda E ME Stricker Thomas P TP Raj Ganesh G Dean Kevin M KM Fiolka Reto R Cantley Lewis C LC Hanker Ariella B AB Arteaga Carlos L CL

Nature communications 20201030 1

The 17q23 amplicon is associated with poor outcome in ER<sup>+</sup> breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER<sup>+</sup> breast cancers. Mechanistically, the proline-ri ...[more]

PMID: 33127913

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Project description:Background: LncRNA is a key factor influencing tumor development. The present study aimed to investigate the effect of a novel lncRNA on the progression of hepatocellular carcinoma (HCC). Methods: A candidate lncRNA in The Cancer Genome Atlas database was identified using limma and survival R packages. The effect of lncRNA AC099850.3 on cell proliferation, apoptosis, migration, and invasion, as well as its association with immune cells in HCC were investigated. Furthermore, the functional mechanisms of lncRNA AC099850.3 in HCC were elucidated. Results: The aberrant expression of lncRNA AC099850.3 was identified in tumor tissues and its prognostic relevance in HCC was determined. The results revealed that AC099850.3 was highly expressed in HCC tissues and cell lines, and it predicted poor prognosis in patients with HCC. Furthermore, knockdown of AC099850.3 significantly suppressed the proliferation and metastatic potential of HCC cells, and promoted cell apoptosis in HCC cells. The results of gene set enrichment analysis revealed that the PI3K/AKT pathway was associated with the biological function of AC099850.3, which was further validated by western blotting. PRR11 was identified as the target gene of AC099850.3 and we established that AC099850.3 acted as an oncogene in the PRR11/PI3K/AKT axis. Immune cell infiltration analyses results revealed that AC099850.3 was positively correlated with T follicular helper cells, M0 macrophages, CD4+ memory T cells, and memory B cells. Conversely, AC099850.3 was negatively correlated with M2 macrophages, monocytes, natural killer cells, and CD8+ T cells, which could be responsible for its oncogenic effect. Of note, a significantly positive correlation was observed between AC099850.3 and key immune checkpoint molecules (PD-1, PD-L1, PD-L2, and CTLA4) in the present study, making AC099850.3 a potential immune therapeutic target for HCC. Conclusion: AC099850.3 can promote malignant biological behavior of HCC cells, and could be a potential biomarker and therapeutic target for HCC.

Project description:IntroductionInsulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth factor receptor and human epidermal growth factor receptor 2. Yet, the direct role of IGF-1R signaling itself in antiestrogen resistance remains obscure. In the present study, we sought to elucidate whether antiestrogen resistance is induced directly by IGF-1R signaling in response to its ligand IGF-1 stimulation.MethodsA breast cancer cell line ectopically expressing human wild-type IGF-1R, MCF7/IGF-1R, was established by retroviral transduction and colony selection. Cellular antiestrogen sensitivity was evaluated under estrogen-depleted two-dimensional (2D) and 3D culture conditions. Functional activities of the key IGF-1R signaling components in antiestrogen resistance were assessed by specific kinase inhibitor compounds and small interfering RNA.ResultsEctopic expression of IGF-1R in ER-positive MCF7 human breast cancer cells enhanced IGF-1R tyrosine kinase signaling in response to IGF-1 ligand stimulation. The elevated IGF-1R signaling rendered MCF7/IGF-1R cells highly resistant to the antiestrogens tamoxifen and fulvestrant. This antiestrogen-resistant phenotype involved mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B pathways downstream of the IGF-1R signaling hub and was independent of ER signaling. Intriguingly, a MAPK/ERK-dependent agonistic behavior of tamoxifen at low doses was triggered in the presence of IGF-1, showing a mild promitogenic effect and increasing ER transcriptional activity.ConclusionsOur data provide evidence that the IGF-1/IGF-1R signaling axis may play a causal role in antiestrogen resistance of breast cancer cells, despite continuous suppression of ER transcriptional function by antiestrogens.

Dataset Information

Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.

Publications

Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.

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