Differential response to exercise in claudin-low breast cancer
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Oliver K. Glass1, Michelle Bowie1, Julie Fuller1, David Darr2, Jerry Usary3, Keara Boss4, Kingshuk Roy Choudhury1, Xioajing Liu1, Zoe Zhang1, Jason W. Locasale1, Christina Williams1, Mark W. Dewhirst1,*, Lee W. Jones5,6,* and Victoria Seewaldt7,*
1 Duke University Medical Center, Durham, NC, USA
2 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3 Arrow Genomics LLC, Chapel Hill, NC, USA
4 North Carolina State University, Raleigh, NC, USA
5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
6 Weill Cornell Medical College, New York, NY, USA
7 City of Hope Cancer Center, Duarte, CA, USA
* These authors have contributed equally to this work
Lee W. Jones, email:
Mark W. Dewhirst, email:
Keywords: exercise, breast cancer, Hif1-α, mouse model, claudin-low
Received: July 18, 2017 Accepted: August 23, 2017 Published: September 19, 2017
Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.
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