Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome. Breast Cancer Res Treat 2019 Aug;177(1):77-91
Date
06/06/2019Pubmed ID
31165373Pubmed Central ID
PMC10317546DOI
10.1007/s10549-019-05307-8Scopus ID
2-s2.0-85066986189 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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 MJAuthors
Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinAmit Joshi PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBiomarkers, 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