The Interplay Between Circadian Clocks and the Tumour Microenvironment in Breast Cancer

TL;DR

This paper reviews how body rhythms (circadian clocks) interact with breast cancer's environment, showing how these rhythms affect cancer growth and treatment timing.

Contribution

The paper introduces circadian timing as a unifying factor linking cell rhythms with breast cancer progression and treatment strategies.

Findings

Circadian rhythms regulate cancer cell processes like DNA repair and metabolism.

Disrupted rhythms from aging or obesity worsen breast cancer progression.

ECM stiffness and circadian changes create feedback loops promoting cancer spread.

Abstract

This review explores how the body’s internal 24 h rhythms, driven by circadian clocks, interact with the microenvironment surrounding a tumour (called the tumour microenvironment (TME)), specifically in breast cancer. While the physical and molecular aspects of cancer are well understood, its temporal dynamics have received less attention. The review outlines how circadian rhythms coordinate crucial cellular biological processes like proliferation, DNA repair, metabolism, and immune surveillance, and how factors such as ageing, chronic stress, and obesity can disrupt these rhythms, contributing to cancer progression. The review extends to a discussion of how the TME, and specifically the biochemical and biophysical properties of the extracellular matrix (ECM), act as a central component mediating this bidirectional control between cell-autonomous rhythms and pro-tumorigenic changes. By understanding these complex temporal connections, the research community can develop new “chronotherapeutic” strategies to reduce the risk of malignancy and time treatments to align with circadian rhythms to improve patient outcomes.

Cancer is a heterogeneous systemic disease that is strongly influenced by dynamic interactions with the tumour microenvironment (TME). Despite major advances in understanding spatial and molecular tumour heterogeneity, the temporal dynamics of tumours have received far less attention. Growing evidence has linked circadian clocks to cancer risk, progression, and treatment response, including in breast cancer. However, temporal regulation has yet to be recognized as a cancer hallmark, and its interaction with the TME remains poorly understood. This review examines how circadian rhythms organize breast cancer biology through bidirectional interactions with the TME. Circadian clocks coordinate proliferation, DNA damage responses, metabolism, and immune surveillance. Ageing, chronic stress, and obesity, all of which are established breast cancer risk modifiers, disrupt these rhythms and are reciprocally exacerbated by circadian dysfunction, establishing feed-forward loops that accelerate disease. Within the TME, the extracellular matrix (ECM) plays a central role in mediating this bidirectional control. Stiffened fibrotic stroma dampens epithelial clock amplitude, while circadian rhythms in turn shape collagen turnover and ECM remodelling. These dynamics can foster inflammation, stem cell expansion, and metastatic dissemination, including time-of-day-dependent release of circulating breast tumour cells. Systemically, circadian clocks gate immune cell trafficking, creating predictable windows of immunosurveillance and therapeutic vulnerability. By integrating insights from mechanobiology, metabolism, immune regulation, and ageing, we position circadian timing as a unifying layer that connects cell-intrinsic programmes with the evolving breast TME. Understanding these connections opens new opportunities for chronotherapeutic strategies in which treatment timing is aligned with circadian rhythms to improve outcomes.

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