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Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity–breast cancer link

International Journal of Obesity volume 42, pages 711–720 (2018)Cite this article

Subjects

Abstract

Background/Objectives:

Obesity (body mass index (BMI)⩾30 kg m−2) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-hypoxia-inducible factor-1α (HIF1α)/pyruvate kinase M2 (PKM2) axis was characterized in adipose stromal cells (ASCs) of women with Li–Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer. The current study aimed to determine whether stimulation of aromatase by obesity-associated adipokine leptin involves the regulation of the p53-HIF1α/PKM2 axis.

Subjects/Methods:

Human breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks.

Results:

Leptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher.

Conclusions:

Overall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

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Acknowledgements

This work was supported by NHMRC project grant (GNT1061800) and Mavis Robertson Fellowship from the National Breast Cancer Foundation (ECF-16-004), as well as NIH R01 CA215797, NIH R01 CA185293, NIH/NCI U54 CA210184-01, the Breast Cancer Research Foundation, the Botwinick-Wolfensohn Foundation (in memory of Mr and Mrs Benjamin Botwinick), the Victorian Government Operational Infrastructure Support Program, Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748) and by Myrna and Bernard Posner. NMI is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology.

Author information

Author notes

  1. H Zahid, K Subbaramaiah, A J Dannenberg and K A Brown: These authors contributed equally to this work.

Authors and Affiliations

  1. Hudson Institute of Medical Research, Clayton, Victoria, Australia

    H Zahid & K A Brown

  2. Faculty of Applied Medical Science, Taibah University, Medina, Saudi Arabia

    H Zahid

  3. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    K Subbaramaiah, N M Iyengar, I-C Chen, P Bhardwaj, A Gucalp, C A Hudis, A J Dannenberg & K A Brown

  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    N M Iyengar, A Gucalp & C A Hudis

  5. Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, USA

    X K Zhou

  6. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    M Morrow

  7. Department of Physiology, Monash University, Clayton, Victoria, Australia

    K A Brown

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Correspondence to A J Dannenberg or K A Brown.

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Zahid, H., Subbaramaiah, K., Iyengar, N. et al. Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity–breast cancer link. Int J Obes 42, 711–720 (2018). https://doi.org/10.1038/ijo.2017.273

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