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

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

doi:10.1007/s10549-019-05307-8

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

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 RuiMichael J. Flister

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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.

Original language	English
Pages (from-to)	77-91
Number of pages	15
Journal	Breast Cancer Research and Treatment
Volume	177
Issue number	1
DOIs	https://doi.org/10.1007/s10549-019-05307-8
State	Published - Aug 30 2019

Keywords

Breast Cancer
Cell cycle
Estrogen
NNAT
Prognosis

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10.1007/s10549-019-05307-8

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Plasterer, C., Tsaih, S. W., Peck, A. R., Chervoneva, I., O’Meara, C., Sun, Y., Lemke, A., Murphy, D., Smith, J., Ran, S., Kovatich, A. J., Hooke, J. A., Shriver, C. D., Hu, H., Mitchell, E. P., Bergom, C., Joshi, A., Auer, P., Prokop, J., ... Flister, M. J. (2019). Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome. Breast Cancer Research and Treatment, 177(1), 77-91. https://doi.org/10.1007/s10549-019-05307-8

@article{5cdf59ecee3544f5915b7835537949c9,

title = "Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome",

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.",

keywords = "Breast Cancer, Cell cycle, Estrogen, NNAT, Prognosis",

author = "Cody Plasterer and Tsaih, {Shirng Wern} and Peck, {Amy R.} and Inna Chervoneva and Caitlin O{\textquoteright}Meara and Yunguang Sun and Angela Lemke and Dana Murphy and Jennifer Smith and Sophia Ran and Kovatich, {Albert J.} and Hooke, {Jeffrey A.} and Shriver, {Craig D.} and Hai Hu and Mitchell, {Edith P.} and Carmen Bergom and Amit Joshi and Paul Auer and Jeremy Prokop and Hallgeir Rui and Flister, {Michael J.}",

note = "Funding Information: This work was supported by a seed grant from the Wisconsin Breast Cancer Showhouse, the MCW Cancer Center, the Advancing a Healthier Wisconsin Endowment, and the Dr. Nancy Laning Sobczak Fund for Breast Cancer (M.J.F, H.R., C.B.). Support was also received from the NCI (R01CA193343 (M.J.F), R01CA188575 (H.R)); the Mary Kay Foundation (Grant No. 024-16 (M.J.F) and 017-29 (C.B.)); the METAvivor Foundation (M.J.F and H.R.); Susan G. Komen Grants KG091116 (H.R., E.P.M, I.C., A.J.K., C.D.S., J.A.H., and H.H.) and CCR17483233 (C.B), an American Cancer Society Institutional Research Grant (#86-004-26 (C.B.)); and the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the Office of the Director of the NIH via the Clinical & Translational Science Institute (#8KL2TR000056 (C.B.)), NIH Office of the Director and NIEHS (K01ES025435 (J.W.P.)). The study was also supported by W81XWH-12-2-0050, HU0001-16-2-0004 from the U.S. Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine (C.D.S., A.J.K., J.A.H., and H.H.). The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army/Navy/Air Force, Department of Defense (DOD), or US Government. Publisher Copyright: {\textcopyright} 2019, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2019",

month = aug,

day = "30",

doi = "10.1007/s10549-019-05307-8",

language = "English",

volume = "177",

pages = "77--91",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

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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 2019, 'Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome', Breast Cancer Research and Treatment, vol. 177, no. 1, pp. 77-91. https://doi.org/10.1007/s10549-019-05307-8

TY - JOUR

T1 - Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome

AU - Plasterer, Cody

AU - Tsaih, Shirng Wern

AU - Peck, Amy R.

AU - Chervoneva, Inna

AU - O’Meara, Caitlin

AU - Sun, Yunguang

AU - Lemke, Angela

AU - Murphy, Dana

AU - Smith, Jennifer

AU - Ran, Sophia

AU - Kovatich, Albert J.

AU - Hooke, Jeffrey A.

AU - Shriver, Craig D.

AU - Hu, Hai

AU - Mitchell, Edith P.

AU - Bergom, Carmen

AU - Joshi, Amit

AU - Auer, Paul

AU - Prokop, Jeremy

AU - Rui, Hallgeir

AU - Flister, Michael J.

N1 - Funding Information: This work was supported by a seed grant from the Wisconsin Breast Cancer Showhouse, the MCW Cancer Center, the Advancing a Healthier Wisconsin Endowment, and the Dr. Nancy Laning Sobczak Fund for Breast Cancer (M.J.F, H.R., C.B.). Support was also received from the NCI (R01CA193343 (M.J.F), R01CA188575 (H.R)); the Mary Kay Foundation (Grant No. 024-16 (M.J.F) and 017-29 (C.B.)); the METAvivor Foundation (M.J.F and H.R.); Susan G. Komen Grants KG091116 (H.R., E.P.M, I.C., A.J.K., C.D.S., J.A.H., and H.H.) and CCR17483233 (C.B), an American Cancer Society Institutional Research Grant (#86-004-26 (C.B.)); and the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the Office of the Director of the NIH via the Clinical & Translational Science Institute (#8KL2TR000056 (C.B.)), NIH Office of the Director and NIEHS (K01ES025435 (J.W.P.)). The study was also supported by W81XWH-12-2-0050, HU0001-16-2-0004 from the U.S. Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine (C.D.S., A.J.K., J.A.H., and H.H.). The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army/Navy/Air Force, Department of Defense (DOD), or US Government. Publisher Copyright: © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2019/8/30

Y1 - 2019/8/30

N2 - 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.

AB - 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.

KW - Breast Cancer

KW - Cell cycle

KW - Estrogen

KW - NNAT

KW - Prognosis

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U2 - 10.1007/s10549-019-05307-8

DO - 10.1007/s10549-019-05307-8

M3 - Article

C2 - 31165373

AN - SCOPUS:85066986189

SN - 0167-6806

VL - 177

SP - 77

EP - 91

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 1

ER -

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

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Keywords

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