American Association for Cancer Research
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FIGURE 5 from Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer

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posted on 2024-05-15, 07:40 authored by Ruizhong Wang, Aditi S. Khatpe, Brijesh Kumar, Henry Elmer Mang, Katie Batic, Adedeji K. Adebayo, Harikrishna Nakshatri

Molecular changes in plasma and skeletal muscles of mice bearing tumors initiated from transformed cell lines. A, Plasma miR-486 levels. B, Skeletal muscle miR-486 levels. C, Skeletal muscle Pax7 mRNA levels. D, Skeletal muscle Myh1 mRNA levels. E, Skeletal muscle p53 mRNA levels. F, Skeletal muscle Pdk4 mRNA levels. G, Skeletal muscle phosphorylated AKT levels. H, Total AKT levels. I, PTEN levels. J, Phosphorylated p-38 levels. K, Total p-38 levels. Quantification of Western blotting was performed using NIH ImageJ software 1.X. Note that in case of TKTB34-PIK3CA, the same blot was probed for AKT and pp38 and, therefore, one Ponceau S blot is shown. Similarly, the same TKTB34-RAS and TKTB6-RAS blot was probed with AKT and p-38 antibodies and one Ponceau S blot is shown.


U.S. Department of Veterans Affairs (VA)

Indiana University Precision Health Initiative



Cancer-induced skeletal muscle defects differ in severity between individuals with the same cancer type. Cancer subtype-specific genomic aberrations are suggested to mediate these differences, but experimental validation studies are very limited. We utilized three different breast cancer patient-derived xenograft (PDX) models to correlate cancer subtype with skeletal muscle defects. PDXs were derived from brain metastasis of triple-negative breast cancer (TNBC), estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) primary breast cancer from a BRCA2-mutation carrier, and pleural effusion from an ER+/PR− breast cancer. While impaired skeletal muscle function as measured through rotarod performance and reduced levels of circulating and/or skeletal muscle miR-486 were common across all three PDXs, only TNBC-derived PDX activated phospho-p38 in skeletal muscle. To further extend these results, we generated transformed variants of human primary breast epithelial cells from healthy donors using HRASG12V or PIK3CAH1047R mutant oncogenes. Mutations in RAS oncogene or its modulators are found in approximately 37% of metastatic breast cancers, which is often associated with skeletal muscle defects. Although cells transformed with both oncogenes generated adenocarcinomas in NSG mice, only HRASG12V-derived tumors caused skeletal muscle defects affecting rotarod performance, skeletal muscle contraction force, and miR-486, Pax7, pAKT, and p53 levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing HRASG12V mutation. Because RAS pathway aberrations are found in 19% of cancers, evaluating skeletal muscle defects in the context of genomic aberrations in cancers, particularly RAS pathway mutations, may accelerate development of therapeutic modalities to overcome cancer-induced systemic effects. Mutant RAS- and PIK3CA-driven breast cancers distinctly affect the function of skeletal muscle. Therefore, research and therapeutic targeting of cancer-induced systemic effects need to take aberrant cancer genome into consideration.

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