TY - JOUR
T1 - Pharmacological dual inhibition of tumor and tumor-induced functional limitations in a transgenic model of breast cancer
AU - Wang, Ruizhong
AU - Bhat-Nakshatri, Poornima
AU - Padua, Maria B.
AU - Prasad, Mayuri S.
AU - Anjanappa, Manjushree
AU - Jacobson, Max
AU - Finnearty, Courtney
AU - Sefcsik, Victoria
AU - McElyea, Kyle
AU - Redmond, Rachael
AU - Sandusky, George
AU - Penthala, Narsimha
AU - Crooks, Peter A.
AU - Liu, Jianguo
AU - Zimmers, Teresa
AU - Nakshatri, Harikrishna
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-17-0717
DO - 10.1158/1535-7163.MCT-17-0717
M3 - Article
C2 - 28978719
AN - SCOPUS:85037679920
SN - 1535-7163
VL - 16
SP - 2747
EP - 2758
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -