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Metabolic pathways in obesity-related breast cancer

Abstract

This Review focuses on the mechanistic evidence for a link between obesity, dysregulated cellular metabolism and breast cancer. Strong evidence now links obesity with the development of 13 different types of cancer, including oestrogen receptor-positive breast cancer in postmenopausal women. A number of local and systemic changes are hypothesized to support this relationship, including increased circulating levels of insulin and glucose as well as adipose tissue-derived oestrogens, adipokines and inflammatory mediators. Metabolic pathways of energy production and utilization are dysregulated in tumour cells and this dysregulation is a newly accepted hallmark of cancer. Dysregulated metabolism is also hypothesized to be a feature of non-neoplastic cells in the tumour microenvironment. Obesity-associated factors regulate metabolic pathways in both breast cancer cells and cells in the breast microenvironment, which provides a molecular link between obesity and breast cancer. Consequently, interventions that target these pathways might provide a benefit in postmenopausal women and individuals with obesity, a population at high risk of breast cancer.

Key points

  • Strong evidence links obesity to the development of 13 types of cancer, including oestrogen receptor-positive breast cancer in postmenopausal women.

  • Metabolic pathways involving PI3K–AKT, HIF1α, LKB1–AMPK and p53 are key regulators of breast cancer cell metabolism and growth.

  • Obesity-associated factors drive metabolic alterations in both breast cancer cells and cells of the breast microenvironment that support tumour growth.

  • Therapies that target metabolic pathways might prove effective at treating and preventing breast cancer via effects on cancer cells, the tumour microenvironment and whole-body metabolism.

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Fig. 1: The breast microenvironment and key drivers of breast cancer in obesity.
Fig. 2: Key metabolic pathways in breast cancer.
Fig. 3: Dysregulated metabolic pathways in breast cancer and adipose stromal cells in the context of obesity.

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Acknowledgements

Research work by K.A.B. is supported by NIH grant R01 CA215797 and the Anne Moore Breast Cancer Research Fund.

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Brown, K.A. Metabolic pathways in obesity-related breast cancer. Nat Rev Endocrinol (2021). https://doi.org/10.1038/s41574-021-00487-0

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