β2-AR signaling controls trastuzumab resistance-dependent pathway

Abstract

Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that β2-adrenergic receptor (β2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and β2-AR affects the bio-behaviors of breast cancer cells, suggesting that the β2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of β2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced β2-AR activation. The data indicate that β2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that β-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of β-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus β-blocker in Her2-overexpressing breast cancer.

Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre‐metastatic niche through activating β‐adrenergic signaling

“…Accumulated evidence indicates that persistent secretion of stress-related hormones and neurotransmitters under chronic stress seriously affects the process of tumor development. Previous studies, including ours, demonstrated that the β2-adrenergic receptor (β2-AR), which mediates the effects of stress-related catecholamines on tumor cells [4], was overexpressed in breast and gastric cancer tissues and that crosstalk between β2-AR and oncogene receptors induced enhanced proliferation signaling in cancer cells [5][6][7]. Aberrant activation of β-adrenergic signaling promoted the growth, invasion, and metastasis of tumors [8].…”

“…Additionally, the safety of β-blocker use has been demonstrated in patients with breast cancer [41]. Our previous study showed that concurrent treatment with a β-blocker and trastuzumab, a monoclonal antibody used as first-line therapy for Her2-overexpressing metastatic breast cancer, significantly improved the progression-free survival and overall survival of patients [6]. The present study demonstrated that inhibition of β-adrenergic signaling reduced the metastatic colonization of the lungs by circulating breast cancer cells, highlighting potentially beneficial effects for the early use of β-blockers in preventing lung metastasis of breast cancer.…”

Tumor suppressor role of miR-3622b-5p in ERBB2-positive cancer

“…ERBB2 induction of migration and invasiveness of cancer cells require the activation of small GTPases and mTORC1 signaling [21–23]. We examined the activation of RhoA, Rac1 and mTORC1 signaling in miR-3622b-5p-transfected cells and control ERBB2-positive cells.…”

Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1

“…Moreover, T-DM1 has recently shown promising results in HER2 þ lung cancer (9). However, despite its significant clinical efficacy, intrinsic and acquired resistance is a major limiting factor for the therapeutic efficacy of T-DM1 (10)(11)(12)(13)(14)(15)(16).…”