Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer.

Autor:	Wang R; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana., Khatpe AS; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana., Kumar B; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana., Mang HE; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana., Batic K; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana., Adebayo AK; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana., Nakshatri H; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.; Richard L Roudebush VA Medical Center, Indianapolis, Indiana.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 May 15; Vol. 4 (5), pp. 1282-1295.
DOI:	10.1158/2767-9764.CRC-24-0045
Abstrakt:	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. Significance: 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. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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