TY - JOUR
T1 - Paget’s disease of the nipple in a Her2-positive breast cancer xenograft model
AU - Drews-Elger, Katherine
AU - Sandoval-Leon, Ana Cristina
AU - Ergonul, Ayse Burcu
AU - Jegg, Anna M.
AU - Gomez-Fernandez, Carmen
AU - Miller, Philip C.
AU - El-Ashry, Dorraya
AU - Lippman, Marc E.
N1 - Funding Information:
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.
Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - HER2
KW - Mouse models of breast disease
KW - Paget’s disease of the nipple
KW - Xenograft models of breast cancer
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U2 - 10.1007/s10549-019-05490-8
DO - 10.1007/s10549-019-05490-8
M3 - Article
C2 - 31720992
AN - SCOPUS:85075079073
VL - 179
SP - 577
EP - 584
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 3
ER -