Abstract # 1825 Beta-adrenergic receptor signaling constrains mammary tumor progression and modulates tumor-associated exosomes

Abstract

Pre-clinical evidence has linked stress exposure to tumor progression via sympathetic nervous system (SNS) activation and beta-adrenergic receptor (beta-AR) signaling. However, retrospective epidemiological studies suggest the association between stress and breast cancer is more ambiguous. To interrogate the impact of stress on the most common type of clinical breast cancer, hormone receptor-positive ductal carcinoma, we used MMTV-PyMT mice, a spontaneous model of metastatic breast cancer. MMTV-PyMT mice were exposed to a stressor featuring chronic social isolation and acute restraint. The combined stressor elicited a prolonged activation of the SNS compared to non-tumor bearing FVB/NJ mice, the MMTV-PyMT background strain. Intriguingly, stress exposure diminished MMTV-PyMT tumor growth, in conjunction with decreased immunosuppressive myeloid-derived suppressor cell frequency and reduced TGF-beta content in circulating tumor-associated exosomes. Blockade of peripheral beta-ARs with the beta-blocker nadolol abrogated stress-induced tumor suppression and restored MDSC frequency and TGF-beta exosomal content. Furthermore, in non-stressed mice, nadolol treatment increased tumor growth and metastasis. These findings suggest (1) mammary tumor progression dysregulates SNS outflow, (2) beta-AR signaling can impede tumor progression, and (3) circulating exosomes may represent biomarkers for the tumor response to beta-AR activation. This work implies that therapeutic outcomes can be optimized by exploiting nervous system regulation of cancer in a patient-specific manner. Funded by NCI Contract No. HHSN261200800001E, DOD W81XWH-13-1-0439.