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

Abstract

<div>Abstract<p>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 <i>miR-486</i> 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 <i>HRAS<sup>G12V</sup></i> or <i>PIK3CA<sup>H1047R</sup></i> mutant oncogenes. Mutations in <i>RAS</i> 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 HRAS<sup>G12V</sup>-derived tumors caused skeletal muscle defects affecting rotarod performance, skeletal muscle contraction force, and <i>miR-486, Pax7</i>, pAKT, and <i>p53</i> levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing <i>HRAS<sup>G12V</sup></i> 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.</p>Significance:<p>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.</p></div>