What is it about?

A plethora of factors contribute to the biochemical underpinnings of breast cancer, in the absence of any clear, integrative framework. This article proposes that melatonergic pathway regulation within mitochondria provides an integrative framework for the wide array of data driving breast cancer pathophysiology. As melatonin is toxic to breast cancer cells, its production within mitochondria poses a significant challenge to breast cancer cell survival. Consequently, the diverse plasticity in breast cancer cells may arise from a requirement to decrease mitochondria melatonin synthesis. The aryl hydrocarbon receptor role in breast cancer pathophysiology may be mediated by an increase in cytochrome P450 (CYP)1b1 in mitochondria, leading to the backward conversion of melatonin to N-acetylserotonin (NAS). NAS has distinct effects to melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation significantly contributes to breast cancer cell survival and migration. However, the most important aspect of NAS induction by CYP1b1 in breast cancer cells is the prevention of melatonin effects in mitochondria. Many of the changes occurring in breast cancer cells arise from the need to regulate this pathway in mitochondria, allowing this to provide a framework that integrates a host of previously disparate data, including: microRNAs, estrogen, 14-3-3 proteins, sirtuins, glycolysis, oxidative phosphorylation, indoleamine 2,3-dioxygenase and the kynurenine pathways. It is also proposed that this framework provides a pathoetiological model incorporating the early developmental regulation of the gut microbiome that integrates breast cancer risk factors, including obesity. This has significant treatment, prevention and research implications.

Featured Image

Why is it important?

This reframes the nature of breast cancer pathophysiology and treatment targets.

Perspectives

The regulation of melatonin production within mitochondria reframes the nature of breast cancers and integrates previously disparate bodies of data.

George Anderson
CRC Scotland & London

Read the Original

This page is a summary of: Breast cancer: Occluded role of mitochondria N-acetylserotonin/melatonin ratio in co-ordinating pathophysiology, Biochemical Pharmacology, October 2019, Elsevier,
DOI: 10.1016/j.bcp.2019.07.014.
You can read the full text:

Read

Contributors

The following have contributed to this page