title: Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.
abstract: OBJECTIVE
  Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease.
  
  
  METHODS
  An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model.
  
  
  RESULTS
  CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR.
  
  
  CONCLUSIONS
  CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Simone
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Tu
authors.initials: T
authors.lastname: Dan
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Palagani
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Lianjin
authors.initials: L
authors.lastname: Jin
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Sunny Y
authors.initials: SY
authors.lastname: Han
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wright
authors.affiliation: b Radiation Oncology Branch , National Cancer Institute , Bethesda , MD , USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Savage
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gitman
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Meng Kieng
authors.initials: MK
authors.lastname: Lim
authors.affiliation: c Department of Pathology , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Palazzo
authors.affiliation: d Radiation Oncology Department , Miami Cancer Institute , Miami , FL , USA.
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.affiliation: a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Simone
mesh_terms: D000818:Animals; D017209:Apoptosis; D031204:Caloric Restriction; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008163:Luminescent Measurements; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy*; D008807:Mice, Inbred BALB C; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011839:Radiation, Ionizing; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014020:Tissue Extracts; D064726:Triple Negative Breast Neoplasms / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy*
chemical_list: D014020:Tissue Extracts; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Caloric restriction; breast cancer; metastases