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HRASG12V, but not PIK3CA-driven variants, induced rotarod, contractile force, and signaling changes. 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[https://doi.org/10.1158/2767-9764.CRC-24-0045](https://doi.org/10.1158/2767-9764.CRC-24-0045)   \nMutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer  \nRuizhong Wang1 , Aditi S. Khatpe1 , 2 , Brijesh Kumar1 , Henry Elmer Mang1 , Katie Batic1 , Adedeji K. Adebayo1 , 2 , and Harikrishna Nakshatri1 , 2 , 3  \nOPEN  \nACCESS  \nCheck for updates  \nABSTRACT  \nCancer-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 triplenegative 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-􀀂􀀃􀀄 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 HRASG􀀅􀀆V or PIK􀀇CAH􀀅􀀈􀀂􀀉R mutant oncogenes. Mutations in RAS oncogene or its modulators are found in approximately 37%  \nof 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-􀀂􀀃􀀄, Pax􀀉, pAKT, and p􀀊􀀇 levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing HRASG􀀅􀀆V 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.  \nSignificance: 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.  \nIntroduction  \nSkeletal muscle dysfunction affects the quality of life of many patients with breast cancer, usually due to role limitations associated with poor physical functioning and body pain. About 39% of patients with breast cancer experience skeletal muscle defects that contribute to mortality in these patients (1) . Clinical data have shown that age, body composition, disease stage, and progression contribute to breast cancer–associated skeletal muscle dysfunction (1–3) . However, there is very limited knowledge regarding how breast cancer subtypes affect skeletal muscle function, although it is believed that aggressive tumor types have greater impact on skeletal muscles of patients (4) .  \n1 Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. 3 Richard L Roudebush VA Medical Center, Indianapolis, Indiana.  \nCorresponding Author: Harikrishna Nakshatri, Indiana University School of Medicine, C218C, 980 West Walnut St. Indianapolis, IN 46202 . E-mail:  \n[hnakshat@iu.edu](hnakshat@iu.edu)  \ndoi: 10.1158/2767-9764 .CRC-24-0045  \nThis open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4 .0) license.  \n© 2024 The Authors; Published by the American Association for Cancer Research  \nRecent preclinical studies by us and others have demonstrated that ","cbCaigZXc7Nqbbhl","https://ap.wps.com/l/cbCaigZXc7Nqbbhl","pdf",16696149,14,"English","# Abstract\n# Significance\n# Introduction\n# Patient-derived xenograft (PDX) models","[{\"question\":\"How did the study assess skeletal muscle defects across breast cancer subtypes?\",\"answer\":\"The research used three patient-derived xenograft (PDX) models and evaluated skeletal muscle function with rotarod performance, alongside molecular changes such as miR levels in circulating and/or muscle tissue.\"},{\"question\":\"Which breast cancer subtype specifically activated phospho-p38 in skeletal muscle?\",\"answer\":\"Only the TNBC-derived PDX activated phospho-p38 in skeletal muscle, whereas impaired function and miR reductions were observed across all three PDXs.\"},{\"question\":\"What distinguishes tumors driven by HRASG12V from those driven by PIK3CAH1047R?\",\"answer\":\"Both oncogene-driven cell variants produced adenocarcinomas in NSG mice, but only HRASG12V-derived tumors caused skeletal muscle defects, including effects on rotarod performance, contraction force, miR levels, and signaling markers in skeletal muscle.\"}]","Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer | PDF",1789996649,35]