Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.

Breast cancer research and treatment 2019 Aug

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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. 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. 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. Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.

Citation

Cody Plasterer, Shirng-Wern Tsaih, Amy R Peck, Inna Chervoneva, Caitlin O'Meara, Yunguang Sun, Angela Lemke, Dana Murphy, Jennifer Smith, Sophia Ran, Albert J Kovatich, Jeffrey A Hooke, Craig D Shriver, Hai Hu, Edith P Mitchell, Carmen Bergom, Amit Joshi, Paul Auer, Jeremy Prokop, Hallgeir Rui, Michael J Flister. Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome. Breast cancer research and treatment. 2019 Aug;177(1):77-91