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Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer

Oncogene volume 33, pages 5729–5739 (2014)Cite this article

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Abstract

Pregnancy-associated breast cancers (PABCs) are tumors diagnosed during pregnancy or up to 5 years following parturition, and are usually high-grade, connective tissue-rich, and estrogen receptor (ER)/progesterone receptor-negative. Little is known about the cellular origin of PABCs or the mechanisms by which PABCs are initiated. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previously reported MMTV-tva transgenic mice, we detected high-grade, poorly differentiated, stroma-rich and ER-negative tumors during pregnancy and lactation. These high-grade and stroma-rich tumors were less frequent in involuted mice or in age-matched nulliparous mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP+ mammary alveolar cells, we found that tumors had similar morphological phenotypes (high grade, poorly differentiated, stroma-rich and ER-negative), irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC.

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Acknowledgements

We acknowledge the Varmus Laboratory for the resources in the generation and initial characterization of WAP-tva mice. This work was supported in part by funds from NIH CA124820 (to YL) and U54CA149196 (to YL; PI: Stephan Wong); from CDMRP BC085050 (to YL) and BC073703 (to YL); NCI U01 CA141582 (to RDC); and from the Nancy Owens Memorial Foundation (to YL); as well as by the resources from the Dan L. Duncan Cancer Center (P30CA125123) and the Sue & Lester Breast Center (P50-CA058183).

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Authors and Affiliations

  1. Lester & Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    S Haricharan, S M Hein, J Dong, M J Toneff & Y Li

  2. Center for Comparative Medicine, University of California at Davis, Davis, CA, USA

    O H Aina & R D Cardiff

  3. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA

    P H Rao

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  1. S Haricharan
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  3. J Dong
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Correspondence to Y Li.

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Haricharan, S., Hein, S., Dong, J. et al. Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer. Oncogene 33, 5729–5739 (2014). https://doi.org/10.1038/onc.2013.521

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