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.
Original language | English (US) |
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Pages (from-to) | 4960-4972 |
Number of pages | 13 |
Journal | Cancer Research |
Volume | 75 |
Issue number | 22 |
DOIs | |
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.
ASJC Scopus subject areas
- Oncology
- Cancer Research