Katherine Drews-Elger1, Ana Cristina Sandoval-Leon1, Ayse Burcu Ergonul2, Anna M Jegg1, Carmen Gomez-Fernandez3, Philip C Miller2,4, Dorraya El-Ashry5,6,7,8, Marc E Lippman9,10,11. 1. Department of Medicine, Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA. 2. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 3970 Reservoir Rd NW, NRB E507A, Miami, FL, 33136, USA. 3. Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA. 4. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, 20007, USA. 5. Department of Medicine, Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA. delashry@bcrf.org. 6. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 3970 Reservoir Rd NW, NRB E507A, Miami, FL, 33136, USA. delashry@bcrf.org. 7. Breast Cancer Research Foundation, 28 West 44th Street, Suite 609, New York, NY, 10036, USA. delashry@bcrf.org. 8. Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. delashry@bcrf.org. 9. Department of Medicine, Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA. mel316@georgetown.edu. 10. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 3970 Reservoir Rd NW, NRB E507A, Miami, FL, 33136, USA. mel316@georgetown.edu. 11. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, 20007, USA. mel316@georgetown.edu.
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.
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.
Entities:
Keywords:
Breast cancer; HER2; Mouse models of breast disease; Paget’s disease of the nipple; Xenograft models of breast cancer