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.