Pharmacological dual inhibition of tumor and tumor-induced functional limitations in a transgenic model of breast cancer

Ruizhong Wang, Poornima Bhat-Nakshatri, Maria B. Padua, Mayuri S. Prasad, Manjushree Anjanappa, Max Jacobson, Courtney Finnearty, Victoria Sefcsik, Kyle McElyea, Rachael Redmond, George Sandusky, Narsimha Penthala, Peter A. Crooks, Jianguo Liu, Teresa Zimmers, Harikrishna Nakshatri

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Breast cancer progression is associated with systemic effects, including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-kB could be central to this process, as it displays oncogenic functions and is integral to the Pax7: MyoD:Pgc-1b:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-kB inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMTþ mice with disease progression. Compared with wild-type mice, tumor-bearing PyMTþ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1b in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6 to 8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1b, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of 6 out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations, and the above-noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations.

Original languageEnglish (US)
Pages (from-to)2747-2758
Number of pages12
JournalMolecular cancer therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, R., Bhat-Nakshatri, P., Padua, M. B., Prasad, M. S., Anjanappa, M., Jacobson, M., Finnearty, C., Sefcsik, V., McElyea, K., Redmond, R., Sandusky, G., Penthala, N., Crooks, P. A., Liu, J., Zimmers, T., & Nakshatri, H. (2017). Pharmacological dual inhibition of tumor and tumor-induced functional limitations in a transgenic model of breast cancer. Molecular cancer therapeutics, 16(12), 2747-2758. https://doi.org/10.1158/1535-7163.MCT-17-0717