Sympathetic activity in breast cancer and metastasis: partners in crime

Abstract

The vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis

“…The safety profile of these drugs is well-described, it is not associated with an increased incidence of breast cancer [230,231], and several clinical and preclinical studies support their use as adjuvant therapy in the treatment of breast cancer [45][46][47][48][49][95][96][97][98][99][100][101][102][232][233][234]. This beneficial effect of β-blockers on breast cancer patient survival, reduction of tumor recurrence, and reduced incidence of metastasis (summarized by Conceição and colleges [58]), remains, however, controversial because most of these studies present limitations, including retrospective design, small population size, difficulty in assessing duration of β-blocker treatment, or lack of data about comorbidities and intake of other medications. Nevertheless, improved relapse-free survival [45] and reduced metastasis and tumor recurrence were observed in breast cancer patients receiving β-blockers [46,48], and consistent with what was observed in some preclinical studies [141], a positive correlation was observed in patients taking propranolol the year before breast cancer diagnosis, specifically regarding tumor invasion and metastatic involvement at diagnosis, as well as reduced cancer-specific mortality [47].…”

“…Results regarding a direct effect of catecholamines or βAR agonists on cancer cells are thus conflicting, but this is to be expected based on the in vitro nature of these assays, the focus on unique cell lines with specific characteristics, and the different doses of drugs used. The expression of αARs and βARs also differs between cancer cells lines and across molecular subtype (ER, PR, and HER2 status, reviewed in [58]). β2AR is the most widely expressed βAR in basal and luminal breast cancer cell lines and in tumor samples from patients with breast cancer [58,[121][122][123].…”

“…The expression of αARs and βARs also differs between cancer cells lines and across molecular subtype (ER, PR, and HER2 status, reviewed in [58]). β2AR is the most widely expressed βAR in basal and luminal breast cancer cell lines and in tumor samples from patients with breast cancer [58,[121][122][123]. β2AR expression was found to correlate with poor prognosis of ER − breast cancer patients [123].…”

“…Over the past two decades, the relevance of skeletal innervation by sympathetic nerves extended to the process of bone metastasis, starting with the observation that chronic stress was associated with enhanced recurrence rates in breast cancer patients, and with metastasis formation, reduced overall survival, and poor patient prognosis [35][36][37][38][39][40][41][42][43][44], whereas β-blocker use was associated with increased relapse-free survival [40,42,[44][45][46][47][48][49]. Chronic stress stimulates activity of the hypothalamic-pituitary axis (HPA) and the sympathetic nervous system (SNS), resulting in the release of norepinephrine (NE) from sympathetic nerve terminals and the stimulation of post-synaptic β-adrenergic receptors (βARs) on target cells, including bone [50] and cancer cells [51][52][53][54][55][56][57] (reviewed in [58]). These clinical observations were the first to support a putative role of excess sympathetic outflow in the mechanisms leading to the successful establishment of disseminated cancer cells into the skeleton.…”

“…Since then, studies in vitro and in preclinical mouse models have refined our understanding of the mechanisms whereby sympathetic nerves can impact the metastatic process, and have revealed the complexity of these mechanisms. The effect of sympathetic nerves on the early stages of metastasis has recently been reviewed [58]. In the present review, we focus more specifically on mechanisms supporting the role of the SNS in the establishment of breast cancer cell metastases in the skeleton, and on how this knowledge supports the potential of βAR blockade as a new therapeutic strategy for a better management of patients with skeletal breast cancer metastases.…”