Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer

Chang, A; Botteri, E; Gillis, RD; Lofling, L; Le, CP; Ziegler, AI; Chung, NC; Rowe, MC; Fabb, SA; Hartley, BJ; Nowell, CJ; Kurozumi, S; Gandini, S; Munzone, E; Montagna, E; Eikelis, N; Phillips, SE; Honda, C; Masuda, K; Katayama, A; Oyama, T; Cole, SW; Lambert, GW; Walker, AK; Sloan, EK

Author(s): Chang, A; Botteri, E; Gillis, RD; Lofling, L; Le, CP; Ziegler, AI; Chung, NC; Rowe, MC; Fabb, SA; Hartley, BJ; Nowell, CJ; Kurozumi, S; Gandini, S; Munzone, E; Montagna, E; Eikelis, N; Phillips, SE; Honda, C; Masuda, K; Katayama, A; Oyama, T; Cole, SW; Lambert, GW; Walker, AK; Sloan, EK;
Details: Publication Year 2023-04-26,Volume 15,Issue #693,Page eadf1147
Journal Title: Science Translational Medicine
Publication Type: Research article
Abstract: Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated beta(2)-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or beta(2)-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting beta(2)-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive beta(2)-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.
Publisher: American Association for the Advancement of Science
Keywords: Humans; Animals; Mice; *Anthracyclines/pharmacology/therapeutic use; *Triple Negative Breast Neoplasms/genetics; Nerve Growth Factor/therapeutic use; Cell Line, Tumor; Neoplasm Recurrence, Local/drug therapy; Receptors, Adrenergic/therapeutic use; Tumor Microenvironment
Department(s): Surgical Oncology
PubMed ID: 37099632
Publisher's Version: https://doi.org/10.1126/scitranslmed.adf1147
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-07-19 07:47:30

Last Modified: 2023-07-19 07:47:59