Problems noted: Functional Limitation (described as muscle weakness, body pain and difficulty in day-to-day activities), sarcopenia with or without accompanying weight loss, and cachexia under metastatic setting, are observed in 39%, 26%, and 25% of breast cancer patients, respectively. Functional limitation, observed even before cancer diagnosis, is the major reason for increased non-cancer related deaths in these patients. Thus, functional limitation is mechanistically concomitant to the paracrine effects of cancer. Sarcopenia impacts not only the functional ability but is also linked to increased toxicity from chemotherapy. While cachexia has received considerable attention because of its phenotypic manifestation, Functional Limitation and sarcopenia have not been studied extensively. Therefore, new model systems to understand the Functional Limitation and sarcopenia in breast cancer and therapeutic strategies are necessary. Preliminary results to resolve the problem: We entered into this field through a serendipitous observation; circulating levels of cardiac and skeletal muscle-enriched miRNA miR-486 were lower in breast cancer patients with metastasis compared to healthy individuals and within experimental models of breast cancer. In animal models, lower circulating miR-486 levels correlated with reduced miR-486 expression in cardiac and skeletal muscle, two primary organs in which it is functionally involved. Moreover, proteins in the myogenesis (MyoD), myotube survival (DOCK3/PTEN/AKT) and cardiomyocyte survival (PI3K/PTEN/pAKT and pp38) networks, that are regulated by and/or regulate miR-486, were deregulated in cardiac and skeletal muscle of tumorbearing transgenic mice compared to controls. Overall, signaling defects in muscle of tumor-bearing animals resembled that of muscular dystrophy mutants (aberrant dystrophin isoforms, lower miR-486, elevated PTEN, and DOCK3). Tumor-derived or recombinant TNF? reduced miR-486 in myogenic and/or cardiomyoblast cell lines. NF-?B and/or p38 kinase, both major signaling molecules downstream of TNF?, are critical in relaying the paracrine effects of cancer, as a constitutively active p65 subunit of NF-?B reduced miR-486 in myogenic cell line. These results extend our previous observations on NF-?B activation in cancer progression, metastasis, and chemoresistance to include cancer-induced systemic functional effects. Hypothesis: Cancer-induced cytokines such as TNF? can impair cardiomyocyte survival and myogenic differentiation via miR-486 deregulation, which leads to Functional Limitation, sarcopenia, cachexia or muscular dystrophy-like phenotype. Thus, circulating miR-486 levels serve as an early predictor of these systemic effects of cancer, which can be exploited not only for diagnostic purpose but also for therapy.
Three aims will test this hypothesis: 1) Determine that cancer disrupts the myogenesis network via miR-486 depletion to cause muscular dystrophy-like condition or sarcopenia; 2) Investigate if NF-?B is a critical signaling relay; and 3) Determine whether circulating miR-486 levels can serve as a putative early indicator of precachexia with accompanying loss of both muscle and fat. Study impact: Although Functional Limitation in breast cancer patients at the time of diagnosis was first reported in 2004, to our knowledge, no mechanistic studies have been conducted since that time, nor have any therapies been developed. Similarly, sarcopenia, which increases chemotherapy-induced toxicity but is not always manifested phenotypically, is well known in breast cancer but therapies have not been developed. The results of this study will have a positive impact by creating new opportunities for rationally interfering with cancer-induced collateral damage to distant organs by repurposing drugs that are already being tested in clinic and prescreening approaches, thereby leading to the discovery of new mechanism-based therapeutic modalities to improve quality of life in cancer patients.

Public Health Relevance

There are limited efforts investigating systemic effects of cancer except cachexia. The proposed studies will conduct mechanistic studies, validate biomarkers of systemic effects, and potentially develop therapies to improve quality of life for cancer patients. Therapies to be tested are already being tested in the clinic for other diseases.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cellular and Molecular Medicine (CAMM)
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Rlr VA Medical Center
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Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko et al. (2018) Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. J Cachexia Sarcopenia Muscle 9:685-700
Wang, Ruizhong; Bhat-Nakshatri, Poornima; Padua, Maria B et al. (2017) Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer. Mol Cancer Ther 16:2747-2758
Beg, Faheemullah; Wang, Ruizhong; Saeed, Zeb et al. (2017) Inflammation-associated microRNA changes in circulating exosomes of heart failure patients. BMC Res Notes 10:751