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Paget’s disease of the nipple in a Her2-positive breast cancer xenograft model

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Paget’s disease (PD) of the breast is an uncommon disease of the nipple usually accompanied by an underlying carcinoma, often HER2 + , and accounting for 0.5–5% of all breast cancer. To date, histogenesis of PD of the breast remains controversial, as two theories—transformation and epidermotropic—have been proposed to explain this disease. Currently, animal models recapitulating PD of the nipple have not been described.

Methods

HER2-enriched DT13 breast cancer cells were injected into the mammary fat pad of NOD scid gamma null (NSG) female mice. Immunohistochemical staining and pathological studies were performed on tumor samples, and diagnosis of PD of the nipple was confirmed by expression of proteins characteristic of Paget cells (epidermal growth factor 2 (HER2), androgen receptor (AR), cytokeratin 7 (CK7), cytokeratin 8/18 (CK8/18), and mucin 1 (MUC1)). In addition, DT13 cells grown in 2D culture and in soft agar assays were sensitive to in vitro treatment with pharmacological inhibitors targeting Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways.

Results

Mice developed tumors and nipple lesions that were detected exclusively on the tumor-bearing mammary fat pad. Tumor cells were positive for proteins characteristic of Paget cells. In vitro, DT13 cells were sensitive to inhibition of Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways.

Conclusions

Our results suggest that injection of HER2 + DT13 cells into the mammary fat pad of NSG mice recapitulates critical aspects of the pathophysiology of PD of the nipple, supporting the epidermotropic theory as the more likely to explain the histogenesis of this disease.

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Abbreviations

PD:

Paget’s disease

NAC:

Nipple-areola complex

HER2:

Human epidermal growth factor receptor 2

ER:

Estrogen receptor

PR:

Progesterone receptor

AR:

Androgen receptor

NSG:

NOD scid gamma null mice

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Funding

This research was supported by NIH Grant 1R01 CA113674 to DEA, Award Number T32CA119929 from the National Cancer Institute supported KDE, and Breast Cancer Research Foundation (BCRF) award to MEL.

Author information

Author notes

  1. Philip C. Miller & Marc E. Lippman

    Present address: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, 20007, USA

  2. Dorraya El-Ashry

    Present address: Breast Cancer Research Foundation, 28 West 44th Street, Suite 609, New York, NY, 10036, USA

  3. Dorraya El-Ashry

    Present address: Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA

Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA

    Katherine Drews-Elger, Ana Cristina Sandoval-Leon, Anna M. Jegg, Dorraya El-Ashry & Marc E. Lippman

  2. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 3970 Reservoir Rd NW, NRB E507A, Miami, FL, 33136, USA

    Ayse Burcu Ergonul, Philip C. Miller, Dorraya El-Ashry & Marc E. Lippman

  3. Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA

    Carmen Gomez-Fernandez

Authors
  1. Katherine Drews-Elger
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  2. Ana Cristina Sandoval-Leon
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  4. Anna M. Jegg
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  6. Philip C. Miller
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  7. Dorraya El-Ashry
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  8. Marc E. Lippman
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Contributions

KDE: designed the study, collected and analyzed the data, and wrote the manuscript; ACSL: contributed to data analysis and writing of the manuscript; AMJ: contributed to data collection and analysis; ABE, CRGF and MEL carried out all diagnoses and pathological interpretations. CRGF, PM, DEA and MEL read and critically revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Dorraya El-Ashry or Marc E. Lippman.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal studies were performed according to a protocol approved by the Institutional Animal Care & Use Committee (IACUC) at the University of Miami.

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Drews-Elger, K., Sandoval-Leon, A.C., Ergonul, A.B. et al. Paget’s disease of the nipple in a Her2-positive breast cancer xenograft model. Breast Cancer Res Treat 179, 577–584 (2020). https://doi.org/10.1007/s10549-019-05490-8

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  • DOI: https://doi.org/10.1007/s10549-019-05490-8

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