title: cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer.
abstract: Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50 mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis.
  
  
  METHODS
  Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29 %, and mean tumor vascularity by 35.04 and 33.52 %, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively.
  
  
  CONCLUSIONS
  Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Alyssa J
authors.initials: AJ
authors.lastname: Cozzo
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Zattra
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Luma
authors.initials: L
authors.lastname: Essaid
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Kirk K
authors.initials: KK
authors.lastname: McNaughton
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: J Ashley
authors.initials: JA
authors.lastname: Ezzell
authors.affiliation: Nutrition Obesity Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|Nutrition Obesity Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
keywords: Hepatocyte growth factor; Microenvironment; Microvascular density; Obesity; Triple negative breast cancer