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Stabilization of prolactin receptor in breast cancer cells

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Abstract

The role of the hormone prolactin (PRL) in the pathogenesis of breast cancer is mediated by its cognate receptor (PRLr). Ubiquitin-dependent degradation of the PRLr that negatively regulates PRL signaling is triggered by PRL-mediated phosphorylation of PRLr on Ser349 followed by the recruitment of the beta-transducin repeats-containing protein (β-TrCP) ubiquitin-protein isopeptide ligase. We report here for the first time that interaction between PRLr and β-TrCP is less efficient in human breast cancer cells than in non-tumorigenic human mammary epithelial cells. Furthermore, we demonstrate that both PRLr degradation and PRLr phosphorylation on Ser349 are impaired in breast tumor cells and tissues, an observation that directly correlates with enhanced expression of the PRLr in malignant breast epithelium. These findings represent a novel mechanism through which altered PRLr stability may directly influence the pathogenesis of breast cancer.

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Abbreviations

PRL:

prolactin

PRLr:

prolactin receptor

β-TrCP:

beta-transducin repeats-containing protein

E3:

ubiquitin-protein isopeptide ligase

HMEC:

human mammary epithelial cells

Stat:

signal transducer and activator of transcription

ICD:

intracellular domain

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Acknowledgements

We thank Drs Ronai, Foster, and Parlow for providing reagents and CHTN and the Tissue Resource Core of the Breast SPORE of the Robert H Lurie Comprehensive Cancer Center of Northwestern University (Chicago, IL, USA) for primary tissues and the array. This work was supported in part by The University of Pennsylvania Cancer Center Pilot Grant and The Susan G Komen Breast Cancer Foundation grant BCTR0504447 (to SYF) and NCI Grant CA069294 (to CVC).

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Authors and Affiliations

  1. Department of Animal Biology, University of Pennsylvania, Philadelphia, PA, USA

    Y Li, N Minkovsky, K G S Kumar & S Y Fuchs

  2. Department of Pathology, Northwestern University, Chicago, IL, USA

    C V Clevenger

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    P N Raghunath & J E Tomaszewski

  4. Department of Dermatology, University of Wisconsin, Madison, WI, USA

    V S Spiegelman

Authors
  1. Y Li
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  2. C V Clevenger
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  3. N Minkovsky
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  4. K G S Kumar
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  5. P N Raghunath
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  6. J E Tomaszewski
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  7. V S Spiegelman
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  8. S Y Fuchs
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Correspondence to S Y Fuchs.

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Li, Y., Clevenger, C., Minkovsky, N. et al. Stabilization of prolactin receptor in breast cancer cells. Oncogene 25, 1896–1902 (2006). https://doi.org/10.1038/sj.onc.1209214

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  • DOI: https://doi.org/10.1038/sj.onc.1209214

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