title: Weight loss reduces basal-like breast cancer through kinome reprogramming.
abstract: BACKGROUND
  Obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). BBC has no targeted therapies, making the need for mechanistic insight urgent. Reducing adiposity in adulthood can lower incidence of BBC in humans. Thus, this study investigated whether a dietary intervention to reduce adiposity prior to tumor onset would reverse HFD-induced BBC.
  
  
  METHODS
  Adult C3(1)-Tag mice were fed a low or high fat diet (LFD, HFD), and an obese group initially exposed to HFD was then switched to LFD to induce weight loss. A subset of mice was sacrificed prior to average tumor latency to examine unaffected mammary gland. Latency, tumor burden and progression was evaluated for effect of diet exposure. Physiologic, histology and proteomic analysis was undertaken to determine mechanisms regulating obesity and weight loss in BBC risk. Statistical analysis included Kaplan-Meier and log rank analysis to investigate latency. Student's t tests or ANOVA compared variables.
  
  
  RESULTS
  Mice that lost weight displayed significantly delayed latency compared to mice fed HFD, with latency matching those on LFD. Plasma leptin concentrations significantly increased with adiposity, were reduced to control levels with weight loss, and negatively correlated with tumor latency. HFD increased atypical ductal hyperplasia and ductal carcinoma in situ in mammary gland isolated prior to mean latency-a phenomenon that was lost in mice induced to lose weight. Importantly, kinome analysis revealed that weight loss reversed HFD-upregulated activity of PKC-α, PKD1, PKA, and MEK3 and increased AMPKα activity in unaffected mammary glands isolated prior to tumor latency.
  
  
  CONCLUSIONS
  Weight loss prior to tumor onset protected against the effects of HFD on latency and pre-neoplastic lesions including atypical ductal hyperplasia and DCIS. Using innovative kinomics, multiple kinases upstream of MAPK/P38α were demonstrated to be activated by HFD-induced weight gain and reversed with weight loss, providing novel targets in obesity-associated BBC. Thus, the HFD-exposed microenvironment that promoted early tumor onset was reprogrammed by weight loss and the restoration of a lean phenotype. Our work contributes to an understanding of underlying mechanisms associated with tumor and normal mammary changes that occur with weight loss.
authors.affiliation: CB 7461, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2203 McGavran Greenberg Hall, Chapel Hill, NC 27599-7461 USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: CB 7461, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2203 McGavran Greenberg Hall, Chapel Hill, NC 27599-7461 USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: CB 7461, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2203 McGavran Greenberg Hall, Chapel Hill, NC 27599-7461 USA.
authors.forename: Luma
authors.initials: L
authors.lastname: Essaid
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Miller
authors.affiliation: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Mouse Phase I Unit, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: CB 7461, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2203 McGavran Greenberg Hall, Chapel Hill, NC 27599-7461 USA ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
keywords: AMPK obesity; Adiposity; Body composition; High fat diet; Kinome; Leptin; MAPK