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 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.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Wright
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Adams
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Loch
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Wong
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christine E B
authors.initials: CE
authors.lastname: Jo
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Beck
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Divya R
authors.initials: DR
authors.lastname: Santhanam
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Weiss
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Xue
authors.initials: X
authors.lastname: Mei
authors.affiliation: Department of Obstetrics and Gynecology and Department of Biological Chemistry, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Lane
authors.affiliation: Department of Pathology, New York University Medical Center, New York, New York.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Done
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. segan@sickkids.ca.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D018631:ras Proteins