Abstract

Obesity is a highly prevalent and modifiable breast cancer risk factor. While the role of obesity in fueling breast cancer progression is well established, the mechanisms linking obesity to breast cancer initiation are poorly understood. A hallmark of breast cancer initiation is the disruption of apical polarity in mammary glands. Here we show that mice with diet-induced obesity display mislocalization of Par3, a regulator of cellular junctional complexes defining mammary epithelial polarity. We found that epithelial polarity loss also occurs in a 3D coculture system that combines acini with human mammary adipose tissue, and establish that a paracrine effect of the tissue adipokine leptin causes loss of polarity by overactivation of the PI3K/Akt pathway. Leptin sensitizes non-neoplastic cells to proliferative stimuli, causes mitotic spindle misalignment, and expands the pool of cells with stem/progenitor characteristics, which are early steps for cancer initiation. We also found that normal breast tissue samples with high leptin/adiponectin transcript ratio characteristic of obesity have an altered distribution of apical polarity markers. This effect is associated with increased epithelial cell layers. Our results provide a molecular basis for early alterations in epithelial architecture during obesity-mediated cancer initiation.

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Acknowledgements

We thank Kenneth Grant for assistance with electron microscopy and Dr. Fei Xing for assistance with stem cell analyses. The CA-Akt construct was a gift from Dr. Mong-Hong Lee (MD Anderson Cancer Center). NuMA B1C11 antibodies were kindly provided by Dr. J. Nickerson (University of Massachusetts). This work was funded by the National Institute of Health (R00CA163957 to PAV), the Walther Cancer Foundation (to SAL, PAV, and IGC), the Wake Forest Center for Molecular Signaling (CMS; to PAV and KB), and the National Cancer Institute’s Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. SAL, VS, and PAV are members of the International Breast Cancer & Nutrition (IBCN) program.

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Author notes

  1. These authors contributed equally: Iliana Tenvooren, Mónica Z. Jenks

Affiliations

  1. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    • Iliana Tenvooren
    • , Mónica Z. Jenks
    • , Hamza Rashid
    • , Julia Holmes
    • , Hui-Wen Lo
    •  & Pierre-Alexandre Vidi
  2. Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    • Katherine L. Cook
  3. Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA

    • Katherine L. Cook
    •  & Pierre-Alexandre Vidi
  4. Department of Biology, Wake Forest University, Winston-Salem, NC, 27109, USA

    • Joëlle K. Muhlemann
  5. Department of Population Sciences, City of Hope, Duarte, CA, 91010, USA

    • Christopher Sistrunk
    •  & Victoria Seewaldt
  6. Department of Physics, Wake Forest University, Winston-Salem, NC, 27109, USA

    • Kevin Wang
    •  & Keith Bonin
  7. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, 45219, USA

    • Kurt Hodges
  8. Indiana University School of Medicine, IU Health Arnett Hospital, Lafayette, IN, 47905, USA

    • Ayaz Shaikh
  9. Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA

    • Ignacio G. Camarillo
  10. Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA

    • Sophie A. Lelièvre

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Conflict of interest

PAV and KB have filed a provisional patent application (No. 62/672,951) on the use of the radial profile method to measure epithelial polarity. The remaining authors declare that they have no conflict of interest.

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Correspondence to Pierre-Alexandre Vidi.

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DOI

https://doi.org/10.1038/s41388-019-0687-8