Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients

Katherine L. Wright; Jessica R. Adams; Jeff C. Liu; Amanda J. Loch; Ruth G. Wong; Christine E.B. Jo; Lauren A. Beck; Divya R. Santhanam; Laura Weiss; Xue Mei; Timothy F Lane; Sergei B. Koralov; Susan J. Done; James R. Woodgett; Eldad Zacksenhaus; Pingzhao Hu; Sean E. Egan

doi:10.1158/0008-5472.CAN-14-2992

Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients

Katherine L. Wright, Jessica R. Adams, Jeff C. Liu, Amanda J. Loch, Ruth G. Wong, Christine E.B. Jo, Lauren A. Beck, Divya R. Santhanam, Laura Weiss, Xue Mei, Timothy F Lane, Sergei B. Koralov, Susan J. Done, James R. Woodgett, Eldad Zacksenhaus, Pingzhao Hu, Sean E. Egan^*

^*Corresponding author for this work

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Abstract

Breast cancer is associated with alterations in a number of growth factor andhormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically featuremutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2⁺ tumors. Incontrast, Ras combined with PIK3CA^H1047R, anoncogenic mutant linked to ERα⁺/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2⁺ subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activationwas strongly linked to reduced survival of patients with ERα⁺ disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα⁺/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.

Original language	English (US)
Pages (from-to)	4960-4972
Number of pages	13
Journal	Cancer Research
Volume	75
Issue number	22
DOIs	https://doi.org/10.1158/0008-5472.CAN-14-2992
State	Published - Nov 15 2015

Funding

The authors thank Jessica Nie, Jodi Garner, Monica Pereira, Sandra Tondat, Sue McMaster, Marina Gertsenstein, Megan Blacquiere, Alex Manno, Leanne Studley, Gessica Raponi, Sisi Li, Nathan Schachter, Jack Plumaj, Abby Tong, Nora Bercovici, andNatalie Gelman for advice and/or technical support; Dr. Keli Xu for advice on mammary tumor studies, Dr. Klaus Rajewsky for Stat3C mice as well as Dr. C.-c. Hui and his lab for advice on use of the R26 transgenic system. The authors also thank members of the Egan, Zacksenhaus and Woodgett labs as well as colleagues at the Hospital for Sick Children. The Egan, Zacksenhaus, and Woodgett labs have been supported by funds from the Terry Fox Foundation. The Egan and Zacksenhaus labs have also been supported by funds from the Canadian Breast Cancer Foundation. The Hu lab has been supported by the Manitoba Medical Services Foundation. This work was financially supported by The Terry Fox Foundation (S.E. Egan, E. Zacksenhaus, and J.R. Woodgett) as well as by the Canadian Breast Cancer Foundation (S.E. Egan and E. Zacksenhaus). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Oncology
Cancer Research

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Wright, K. L., Adams, J. R., Liu, J. C., Loch, A. J., Wong, R. G., Jo, C. E. B., Beck, L. A., Santhanam, D. R., Weiss, L., Mei, X., Lane, T. F., Koralov, S. B., Done, S. J., Woodgett, J. R., Zacksenhaus, E., Hu, P., & Egan, S. E. (2015). Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients. Cancer Research, 75(22), 4960-4972. https://doi.org/10.1158/0008-5472.CAN-14-2992

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title = "Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients",

abstract = "Breast cancer is associated with alterations in a number of growth factor andhormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically featuremutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2+ tumors. Incontrast, Ras combined with PIK3CAH1047R, anoncogenic mutant linked to ERα+/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2+ subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activationwas strongly linked to reduced survival of patients with ERα+ disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα+/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.",

author = "Wright, {Katherine L.} and Adams, {Jessica R.} and Liu, {Jeff C.} and Loch, {Amanda J.} and Wong, {Ruth G.} and Jo, {Christine E.B.} and Beck, {Lauren A.} and Santhanam, {Divya R.} and Laura Weiss and Xue Mei and Lane, {Timothy F} and Koralov, {Sergei B.} and Done, {Susan J.} and Woodgett, {James R.} and Eldad Zacksenhaus and Pingzhao Hu and Egan, {Sean E.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Association for Cancer Research.",

year = "2015",

month = nov,

day = "15",

doi = "10.1158/0008-5472.CAN-14-2992",

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Wright, KL, Adams, JR, Liu, JC, Loch, AJ, Wong, RG, Jo, CEB, Beck, LA, Santhanam, DR, Weiss, L, Mei, X, Lane, TF, Koralov, SB, Done, SJ, Woodgett, JR, Zacksenhaus, E, Hu, P & Egan, SE 2015, 'Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients', Cancer Research, vol. 75, no. 22, pp. 4960-4972. https://doi.org/10.1158/0008-5472.CAN-14-2992

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T1 - Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients

AU - Wright, Katherine L.

AU - Adams, Jessica R.

AU - Liu, Jeff C.

AU - Loch, Amanda J.

AU - Wong, Ruth G.

AU - Jo, Christine E.B.

AU - Beck, Lauren A.

AU - Santhanam, Divya R.

AU - Weiss, Laura

AU - Mei, Xue

AU - Lane, Timothy F

AU - Koralov, Sergei B.

AU - Done, Susan J.

AU - Woodgett, James R.

AU - Zacksenhaus, Eldad

AU - Hu, Pingzhao

AU - Egan, Sean E.

PY - 2015/11/15

Y1 - 2015/11/15

N2 - Breast cancer is associated with alterations in a number of growth factor andhormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically featuremutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2+ tumors. Incontrast, Ras combined with PIK3CAH1047R, anoncogenic mutant linked to ERα+/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2+ subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activationwas strongly linked to reduced survival of patients with ERα+ disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα+/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.

AB - Breast cancer is associated with alterations in a number of growth factor andhormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically featuremutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2+ tumors. Incontrast, Ras combined with PIK3CAH1047R, anoncogenic mutant linked to ERα+/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2+ subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activationwas strongly linked to reduced survival of patients with ERα+ disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα+/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.

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Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients

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