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PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer

Oncogene volume 27, pages 4657–4665 (2008)Cite this article

Abstract

Carcinoma is an altered state of tissue differentiation in which epithelial cells no longer respond to cues that keep them in their proper position. A break down in these cues has disastrous consequences not only in cancer but also in embryonic development when cells of various lineages must organize into discrete entities to form a body plan. Paraxial protocadherin (PAPC) is an adhesion protein with six cadherin repeats that organizes the formation and polarity of developing cellular structures in frog, fish and mouse embryos. Here we show that protocadherin-8 (PCDH8), the human ortholog of PAPC, is inactivated through either mutation or epigenetic silencing in a high fraction of breast carcinomas. Loss of PCDH8 expression is associated with loss of heterozygosity, partial promoter methylation, and increased proliferation. Complementation of mutant tumor cell line HCC2218 with wild-type PCDH8 inhibited its growth. Two tumor mutants, E146K and R343H, were defective for inhibition of cell growth and migration. Surprisingly, the E146K mutant transformed the human mammary epithelial cell line MCF10A and sustained the expression of cyclin D1 and MYC without epidermal growth factor. We propose that loss of PCDH8 promotes oncogenesis in epithelial human cancers by disrupting cell–cell communication dedicated to tissue organization and repression of mitogenic signaling.

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Acknowledgements

We thank Tom Jessell and Stephen Price for suggestions and assistance with in situ hybridization. We thank Michael R Stratton and Graham R Bignell for their help in mapping the break points of the homozygous deletion in HCC1395. We also thank Vimla Band, Gary Nolan, Scott Lowe, Joan Brugge, Nancy Hynes for reagents and Larry Shapiro for assistance in the analysis of coding changes. JSY received support from NIH and NCI and RP received support from Avon Foundation, Octoberwoman Foundation, and NCI. HH received support from Avon Foundation.

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Author notes

  1. S Nagase

    Present address: 4Current address: Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Seiryo-machi, Miyagi, Japan.,

  2. L Memeo

    Present address: 5Current address: Department of Experimental Oncology, Mediterranean Institute of Oncology Via Penninazzo, Viagrande (CT), Italy.,

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, NY, USA

    J S Yu, S Koujak, S Nagase, C-M Li, M Keniry, B Tycko & R Parsons

  2. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    J S Yu, T Su, X Wang, L Memeo, A Rojtman, M Mansukhani, H Hibshoosh, B Tycko & R Parsons

  3. Department of Medicine, Columbia University, New York, NY, USA

    R Parsons

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  1. J S Yu
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Correspondence to R Parsons.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Yu, J., Koujak, S., Nagase, S. et al. PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene 27, 4657–4665 (2008). https://doi.org/10.1038/onc.2008.101

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  • DOI: https://doi.org/10.1038/onc.2008.101

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