title: Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors.
abstract: The causes for malignant progression of disseminated tumors and the reasons recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and show that recurrence rates are not strictly due to cell-intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer. Systemic signals provided by overt TNBCs cause the formation of a tumor-supportive microenvironment enriched for EGF and insulin-like growth factor-I (IGF-I) at distant indolent tumor sites. Bioavailability of EGF and IGF-I enhances the expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGF receptor and IGF-I receptor inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC.
authors.affiliation: Hematology Division , Brigham & Women's Hospital, Lund University, Lund, Sweden.
authors.forename: Zafira
authors.initials: Z
authors.lastname: Castaño
authors.forename: Timothy
authors.initials: T
authors.lastname: Marsh
authors.forename: Ramya
authors.initials: R
authors.lastname: Tadipatri
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Kuznetsov
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Paktinat
authors.forename: April
authors.initials: A
authors.lastname: Greene-Colozzi
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McAllister
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1