Exploring neurotransmitters and their receptors for breast cancer prevention and treatment

Abstract

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance. Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways. Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment. However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects. In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors. In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer. Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells. Moreover, we discuss findings where clinical agents used to treat neurological and/or psychological disorders have exhibited preventive/therapeutic effects against breast cancer in either associative or pre-clinical studies. Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types. We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement.

Keywords: Breast cancer; Nerves; Neurotransmitter receptors; Neurotransmitters; Tumor microenvironments.

Figure 1

Schematic illustration of innervation of the breast. T04: the fourth thoracic nerve; T05: the fifth thoracic nerve; T06: the sixth thoracic nerve; IV: the fourth intercostal nerve; V: the fifth intercostal nerve; VI: the sixth intercostal nerve.

Figure 2

Classification of adrenergic receptors (ARs) and the major downstream effectors of individual AR subtypes. AC, Adenylyl cyclase; cAMP, cyclic adenosine monophosphate; DAG, diacyl glycerol; IP3, inositol 1,4,5-trisphosphate; PKA, protein kinase A; PLC, phospholipase C.

Figure 3

Classification of acetylcholine (ACh) receptors (AChRs) and the major downstream signal pathways of individual AChR subtypes. AC, Adenylyl cyclase; cAMP, cyclic adenosine monophosphate; mAChRs, muscarinic AChRs; nAChRs, nicotinic AChRs; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNN, N′- nitrosonornicotine; NOS, nitric oxide synthase; PKA, protein kinase A; PLA2, phospholipase A2; PLC, Phospholipase C; PPM1F, protein phosphatase 1F.

Figure 4

Classification of dopamine (DA) receptors (DARs) and the major downstream signal pathways of individual DARs. AC, Adenylyl cyclase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; D1R-like receptors, DA type1-like receptors; D2R-like receptors, DA type 2-like receptors; GC, guanylate cyclase; PKA, protein kinase A; PKG, protein kinase G; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor.

Figure 5

Classification of 5-hydroxytryptamine (5-HT) receptors (5-HTRs) and the major downstream signal pathways of individual 5-HTRs. AC, Adenylyl cyclase; ATF1, activating transcription factor 1; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; JAK1, Janus kinase 1; MMP2, matrix metalloproteinase-2; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKM2, pyruvate kinase M2; STAT3, signal transducer and activator of transcription 3; TPH1, tryptophan hydroxylase 1; VEGF, Vascular endothelial growth factor.

Figure 6

Classification of glutamate (Glu) receptors (GluRs) and the major downstream signal pathways of individual GluRs. AC, Adenylyl cyclase; AMPAR, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; iGluRs, ionotropic Glu receptors; IP3, Inositol trisphosphate; KR, kainate receptor; mGluRs, metabotropic Glu receptors; NMDAR, N-methyl-D-aspartate receptor; PKC, Protein kinase C; PLC, Phospholipase C.