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  • Review Article
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Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy

Nature Reviews Endocrinology volume 20, pages 16–26 (2024)Cite this article

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Abstract

Breast cancer is the most common invasive malignancy in the world, with millions of survivors living today. Type 2 diabetes mellitus (T2DM) is also a globally prevalent disease that is a widely studied risk factor for breast cancer. Most breast tumours express the oestrogen receptor and are treated with systemic therapies designed to disrupt oestrogen-dependent signalling. Since the advent of targeted endocrine therapy six decades ago, the mortality from breast cancer has steadily declined; however, during the past decade, an elevated risk of T2DM after breast cancer treatment has been reported, particularly for those who received endocrine therapy. In this Review, we highlight key events in the history of endocrine therapies, beginning with the development of tamoxifen. We also summarize the sequence of reported adverse metabolic effects, which include dyslipidaemia, hepatic steatosis and impaired glucose tolerance. We discuss the limitations of determining a causal role for breast cancer treatments in T2DM development from epidemiological data and describe informative preclinical studies that suggest complex mechanisms through which endocrine therapy might drive T2DM risk and progression. We also reinforce the life-saving benefits of endocrine therapy and highlight the need for better predictive biomarkers of T2DM risk and preventive strategies for the growing population of breast cancer survivors.

Key points

  • Endocrine therapies for breast cancer might increase the risk of type 2 diabetes mellitus (T2DM) development in some patients.

  • Oestrogens and oestrogen receptor activation protect against metabolic disease and are disrupted with breast cancer treatment.

  • Tamoxifen treatment promotes dyslipidaemia and hepatic steatosis in some people and also has adipose-specific effects in preclinical and clinical studies.

  • One paradigm of T2DM development centres on dysfunctional adipose tissue expansion.

  • Preclinical studies indicate that adipose tissue might be an early target of endocrine therapies for breast cancer.

  • Endocrine therapies save lives, so an urgent need exists to understand any associated T2DM risk and offer interventions for patients with breast cancer.

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Fig. 1: The vicious cycle surrounding T2DM and breast cancer.
Fig. 2: A brief history of endocrine therapy for breast cancer.
Fig. 3: ER expression in peripheral metabolic tissues.
Fig. 4: Proposed model of adipose tissue as an early target of endocrine therapy.

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Acknowledgements

The authors are grateful for the guidance of S. Wright-Hobart, a breast cancer survivor and patient advocate. Her experience with breast cancer therapy and that of her fellow survivors provide a critical perspective and inspired this line of work in our laboratories. N.S.T. acknowledges the support of the Harold Hamm Diabetes Center and Stephenson Cancer Center postdoctoral fellowship, and E.A.W. acknowledges the support of the Human Environmental Sciences Institute THRIVE grant.

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Authors and Affiliations

  1. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Nisha S. Thomas & Elizabeth A. Wellberg

  2. Stephenson Cancer Center, Oklahoma City, OK, USA

    Nisha S. Thomas & Elizabeth A. Wellberg

  3. Harold Hamm Diabetes Center, Oklahoma City, OK, USA

    Nisha S. Thomas & Elizabeth A. Wellberg

  4. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Rebecca L. Scalzo

  5. Rocky Mountain Regional VA Medical Center, Aurora, CO, USA

    Rebecca L. Scalzo

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Thomas, N.S., Scalzo, R.L. & Wellberg, E.A. Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy. Nat Rev Endocrinol 20, 16–26 (2024). https://doi.org/10.1038/s41574-023-00899-0

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