Abstract P6-15-03: Dual targeting of mammary tumors and tumor-associated functional limitations through inhibition of NF-kB
Authors: Wang R , Nakshatri P , Padua MB , Anjanappa M , Penthala N , Crook PA , Liu J , Zimmers T , Nakshatri H 
Published: March 2017

Breast cancer progression is associated with systemic effects such as functional limitation, sarcopenia and cachexia. These effects are manifested as muscle weakness, body pain or depletion of skeletal muscle mass. Over a quarter of 2.8 million breast cancer patients in the United States experience a precachexia to cachexia syndrome. It has been reported that cancer-induced cytokines activate NF-κB, which promotes cancer progression, metastasis, and chemoresistance. These cytokines could potentially induce NF-kB in skeletal muscle, impair skeletal muscle function, and cause functional limitations. Therefore, NF-κB inhibitors could serve dual purpose of inhibiting cancer progression and reducing functional limitations. In present study, we usedMMTV-PyMT transgenic mammary tumor model to test therapeutic effects of the NF-κB inhibitor, Diaminomethylparthenolide (DMAPT), an orally bioavailable NF-kB inhibitor. We observed deteriorating physical and functional conditions in PyMT+ mice with the progression of mammary tumor.Compared to wildtype mice, PyMT+ mice with mammary tumors showed decreased fat mass and grip strength, both are markers of functional limitations. Treatment with DMAPT (100mg/kg, 5 times/week, orally), starting at 8 week-old prior to mammary tumor occurrence, delayed mammary tumor onset and slowed tumor growth rates compared to vehicle treatment. Consequently, DMAPT-treated mice showed lower systemic effects of mammary tumors on grip strength and alterations of body compositions (i.e. body fat, lean mass). Moreover, systemic treatment with DMAPT significantly increased survival trends in PyMT+ mice. These results suggest that NF-κB is a critical signaling relay engaged by paracrine effects of breast cancer on skeletal muscle function. Mechanistic studies in vitro suggested that cancer-induced cytokines specifically target microRNAs in skeletal muscle.miR486 is a muscle-enriched microRNA that controls differentiation of myoblasts. In particularly, conditioned media from a number of mammary tumor cell lines, including PO1058 (poorly invasive tumor cells from PyMT-WapCre-mGFP+ mice in C57BL6 background) and PO1059 (highly invasive cells from PyMT-WapCre-mGFP+ mice) reduced the levels of miR486 in the myoblast cells C2C12. Literature demonstrated that reduced miR486 in muscle is linked to musculoskeletal defects in muscular dystrophy patients. These data are consistent with previous studies in which lower circulating miR486 occurred in plasma of breast cancer patients with metastasis compared with healthy women, and as well in skeletal muscle of mammary tumor bearing animals. Further studies are essential to establish a cancer-induced cytokine, NF-kB activation in muscle, deregulated expression and release of miR486 from muscle and cancer-associated systemic effects circuitry. In summary, mammary tumors result in changes in body composition with decreased grip strength, which may be associated with altered NF-κB signaling pathways, and NF-κB inhibitor DMAPT can be used as a potential candidate for the treatment of breast cancer and associated functional limitations to improve the quality of life. Additionally, circulating miR486 may serve as a useful clinical indicator of progression and systemic effects of breast cancer.

Citation Format: Wang R, Nakshatri P, Padua MB, Anjanappa M, Penthala N, Crook PA, Liu J, Zimmers T, Nakshatri H. Dual targeting of mammary tumors and tumor-associated functional limitations through inhibition of NF-kB [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-15-03.