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Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome. Breast Cancer Res Treat 2019 Aug;177(1):77-91

Date

06/06/2019

Pubmed ID

31165373

DOI

10.1007/s10549-019-05307-8

Scopus ID

2-s2.0-85066986189

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.

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.

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.

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.

Author List

Plasterer C, Tsaih SW, Peck AR, Chervoneva I, O'Meara C, Sun Y, Lemke A, Murphy D, Smith J, Ran S, Kovatich AJ, Hooke JA, Shriver CD, Hu H, Mitchell EP, Bergom C, Joshi A, Auer P, Prokop J, Rui H, Flister MJ

Authors

Amit Joshi PhD Associate Professor in the Biomedical Engineering department at Medical College of Wisconsin
Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Biomarkers, Tumor
Breast Neoplasms
Cell Line, Tumor
Disease Models, Animal
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes, Modifier
Humans
Immunohistochemistry
Incidence
Kaplan-Meier Estimate
Membrane Proteins
Neoplasm Staging
Nerve Tissue Proteins
Patient Outcome Assessment
Prognosis
Rats
Receptors, Estrogen
Signal Transduction
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a