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Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.
- Source :
-
Breast cancer research and treatment [Breast Cancer Res Treat] 2019 Aug; Vol. 177 (1), pp. 77-91. Date of Electronic Publication: 2019 Jun 04. - Publication Year :
- 2019
-
Abstract
- Purpose: Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer.<br />Experimental Design: Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer. Tumors from susceptible and resistant congenics were analyzed by RNAseq to identify candidate genes. Candidates were prioritized by correlation with outcome, using a consensus of three breast cancer patient cohorts. NNAT was transgenically expressed in ER+ breast cancer lines (T47D and ZR75), followed by transcriptomic and phenotypic characterization.<br />Results: We identified a region on rat chromosome 3 (142-178 Mb) that modified mammary tumor incidence. RNAseq of the mammary tumors narrowed the candidate list to three differentially expressed genes: NNAT, SLC35C2, and FAM210B. NNAT mRNA and protein also correlated with survival in human breast cancer patients. Quantitative immunohistochemistry of NNAT protein revealed an inverse correlation with survival in a univariate analysis of patients with invasive ER+ breast cancer (training cohort: n = 444, HR = 0.62, p = 0.031; validation cohort: n = 430, HR = 0.48, p = 0.004). NNAT also held up as an independent predictor of survival after multivariable adjustment (HR = 0.64, p = 0.038). NNAT significantly reduced proliferation and migration of ER+ breast cancer cells, which coincided with altered expression of multiple related pathways.<br />Conclusions: Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.
- Subjects :
- Animals
Biomarkers, Tumor
Breast Neoplasms mortality
Breast Neoplasms pathology
Cell Line, Tumor
Disease Models, Animal
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Incidence
Kaplan-Meier Estimate
Membrane Proteins metabolism
Neoplasm Staging
Nerve Tissue Proteins metabolism
Patient Outcome Assessment
Prognosis
Rats
Receptors, Estrogen metabolism
Signal Transduction
Breast Neoplasms epidemiology
Breast Neoplasms etiology
Genes, Modifier
Membrane Proteins genetics
Nerve Tissue Proteins genetics
Receptors, Estrogen genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7217
- Volume :
- 177
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Breast cancer research and treatment
- Publication Type :
- Academic Journal
- Accession number :
- 31165373
- Full Text :
- https://doi.org/10.1007/s10549-019-05307-8