High nerve density in breast cancer is associated with poor patient outcome

Abstract

Background: Active crosstalk between the nervous system and breast cancer cells as well as other cell types within the tumour microenvironment has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to better define the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features.Methods: Immunohistochemical staining was conducted in formalin-fixed paraffin-embedded breast cancer tissue sections using antibodies against the pan-neuronal markers protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), and the sympathetic nerve-specific marker tyrosine hydroxylase (TH). Nerve trunks (comprised of many nerve fibres/axons) and isolated nerve fibres (positively stained cells with or without typical morphology of axons outside definable nerve trunks) were quantitated. The chi-squared test was used to determine the associations between nerve trunk or isolated nerve fibre counts and clinicopathological parameters. The Log-rank test was used to compare differences in patient progression-free survival (PFS) and overall survival (OS). A multivariate analysis was performed according to the Cox Proportional Hazards Model to assess independent prognostic factors.Results: Nerve trunks and isolated nerve fibres were detected in 75% and 77% of breast cancers, respectively. The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin (positive for TH). While high density of nerve trunks or isolated nerve fibres was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Conclusions: Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.

Contribution of adrenergic mechanisms for the stress‐induced breast cancer carcinogenesis

“…In breast tumors, the presence of tyrosine hydroxylase‐positive immunoreactivity was demonstrated, both in tumor and in nontumor stromal areas (Kamiya et al, 2019; Szpunar et al, 2016). Their density varies widely between studies (D. Li et al, 2021; Szpunar et al, 2016) what suggests that catecholamine synthesis within the tumor may be a dynamic process and vary according to the progression stage of breast cancer, being higher in early tumor growth (Szpunar et al, 2016). This pattern was demonstrated by Mercedes and colleagues (Szpunar et al, 2016), who showed that in MMTV‐PyMT mice, a model that closely mimics clinical breast cancer stages, the sympathetic nerve fibers innervation was higher in early premalignant masses comparatively to that observed in later‐stage adenocarcinomas.…”