Abstract
Breast cancer is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically feature mutated 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. In contrast, Ras combined with PIK3CA(H1047R), an oncogenic 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 activation was 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.
Highlights
Ras genes are mutated in a relatively small percentage of human breast cancers
As transformation by mutant PIK3CA can be dependent on tyrosine phosphorylation of Stat3 [30], and activated Stat3 is associated with metastatic dissemination in some contexts [18,19,20], we tested for cooperation between Pik3caH1047R and Stat3A661C/N663C [31]
Ras cooperates with mutant Pik3ca or Stat3 to induce metastatic mammary adenocarcinoma Mammary tumors that form in Pik3caH1047R mice had a very low rate of lung metastasis (3/51 mice had one or two mets each, see Fig. 5A)
Summary
Ras genes are mutated in a relatively small percentage of human breast cancers. Ras signaling can be activated through copy number changes or mutation of many genes, including those. Additional and refined subtypes have been identified through incorporation of data on mutations and copy number alterations [9] and comparison to specific mammary epithelial cell types [10] These different forms of breast cancer progress through different mechanisms, and poor prognosis in each subtype can be linked to alterations in distinct signaling pathways or transcriptional programs. The tumors that form in Pik3ca, as well as in Pik3ca/p53 double mutant mice, do not metastasize at a high rate These data suggest that PIK3CAmutant alleles may cooperate with distinct signaling pathways to induce metastatic ERaþ breast cancer. In an effort to define the relationship between oncogenic pathway activation and breast cancer subtype, as well as metastatic dissemination, we generated mouse models for breast cancer with elevated PI3K, Stat, and/or Ras signaling. We used pathway-specific gene signatures to test for linkage of elevated PI3K, Stat, and Ras to relapse and survival in humans
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