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Cancer Cell International
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

Weight loss reduces basal-like breast cancer through kinome reprogramming

Authors: Yuanyuan Qin, Sneha Sundaram, Luma Essaid, Xin Chen, Samantha M. Miller, Feng Yan, David B. Darr, Joseph A. Galanko, Stephanie A. Montgomery, Michael B. Major, Gary L. Johnson, Melissa A. Troester, Liza Makowski

Published in: Cancer Cell International | Issue 1/2016

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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.
Appendix
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Metadata
Title
Weight loss reduces basal-like breast cancer through kinome reprogramming
Authors
Yuanyuan Qin
Sneha Sundaram
Luma Essaid
Xin Chen
Samantha M. Miller
Feng Yan
David B. Darr
Joseph A. Galanko
Stephanie A. Montgomery
Michael B. Major
Gary L. Johnson
Melissa A. Troester
Liza Makowski
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0300-y

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