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Ovarian hyperstimulation induces centrosome amplification and aneuploid mammary tumors independently of alterations in p53 in a transgenic mouse model of breast cancer

Oncogene volume 27, pages 1759–1766 (2008)Cite this article

Abstract

Aneuploidy and genomic instability are common features of human cancers, including breast cancer; however, mechanisms by which such abnormalities develop are not understood. The exquisite dependence of the mammary gland on hormones for growth and development as well as hormonal contributions to breast cancer risk and progression suggest that tumorigenic mechanisms in the breast should be considered in the context of hormonal stimulation. We used transgenic mice that overexpress luteinizing hormone with subsequent ovarian hyperstimulation as a model to identify mechanisms involved in hormone-induced mammary cancer. Tumor pathology in these mice is highly variable, suggesting individual tumors undergo distinct initiating or promoting events. Supporting this notion, hormone-induced tumors display considerable chromosomal instability and aneuploidy, despite the presence of functional p53. The presence of extensive centrosome amplification in tumors and hyperplastic glands prior to tumor formation suggests that alterations in the ovarian hormonal milieu dysregulate the centrosome cycle in mammary epithelial cells, leading to aneuploidy and cancer.

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Acknowledgements

Core facilities of the Case Comprehensive Cancer Center (P30 CA43703) provided valuable services for real time RT–PCR and radiation of mice. We thank Guan-bin Lou and Ellen Barnes for their technical advice regarding metaphase spread preparation, Lindsey Mayo for thoughtful discussions regarding p53, and Kshama Mehta from Agilent Technologies Center of Excellence for performing CGH analysis and assistance with data mining. This work was funded by USAMRMC grant DAMD 17-01-1-0195, NIH Grant CA090398 (to RAK), NIH Training Grants T32GM08056 (to ELM), T32GM08803 (to MDL) and T32CA059366 (to EJ), and a predoctoral traineeship, DAMD17-03-1-0302, from the USAMRMC (to MDL).

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Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    E L Milliken, K L Lozada, E Johnson, M D Landis, D D Seachrist, I Whitten, A L M Sutton & R A Keri

  2. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    F W Abdul-Karim

  3. Department of Pathology, University Hospitals of Cleveland, Cleveland, OH, USA

    F W Abdul-Karim

  4. Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    R A Keri

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  1. E L Milliken
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  2. K L Lozada
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Correspondence to R A Keri.

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

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Milliken, E., Lozada, K., Johnson, E. et al. Ovarian hyperstimulation induces centrosome amplification and aneuploid mammary tumors independently of alterations in p53 in a transgenic mouse model of breast cancer. Oncogene 27, 1759–1766 (2008). https://doi.org/10.1038/sj.onc.1210815

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