An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer

Autor: Maihi Fujita, Alana L. Welm, Zheqi Li, Steffi Oesterreich, Yoko S. DeRose, Jennifer Toner, Alessandra I. Riggio, Ahmed A. Samatar, Fadi Haroun, Ling Zhao, H. Atakan Ekiz, Sandra D. Scherer
Jazyk: angličtina
Rok vydání: 2021
Předmět:
ER+ PDX
Antigens
CD34
Breast Neoplasms
Mice
Transgenic
Mice
SCID
Estrogen supplementation
Mice
Breast cancer
Surgical oncology
Mice
Inbred NOD
medicine
Tumor Microenvironment
Animals
Humans
Humanized PDX
skin and connective tissue diseases
RC254-282
Tumor microenvironment
business.industry
Y537S
Estrogen Receptor alpha
Hematopoietic Stem Cell Transplantation
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cancer
ER+ metastatic breast cancer
Immune-humanization
Estrogens
medicine.disease
Hematopoietic Stem Cells
Metastatic breast cancer
ESR1 mutation
Xenograft Model Antitumor Assays
Breast cancer tumor microenvironment
Disease Models
Animal
medicine.anatomical_structure
Receptors
Estrogen
Tumor progression
Drug Resistance
Neoplasm
Mutation
Cancer research
bacteria
Heterografts
Female
Bone marrow
business
Estrogen receptor alpha
Research Article
Endocrine resistance model
Zdroj: Breast Cancer Research : BCR
Breast Cancer Research, Vol 23, Iss 1, Pp 1-18 (2021)
ISSN: 1465-542X
1465-5411
Popis: Background Metastatic breast cancer (MBC) is incurable, with a 5-year survival rate of 28%. In the USA, more than 42,000 patients die from MBC every year. The most common type of breast cancer is estrogen receptor-positive (ER+), and more patients die from ER+ breast cancer than from any other subtype. ER+ tumors can be successfully treated with hormone therapy, but many tumors acquire endocrine resistance, at which point treatment options are limited. There is an urgent need for model systems that better represent human ER+ MBC in vivo, where tumors can metastasize. Patient-derived xenografts (PDX) made from MBC spontaneously metastasize, but the immunodeficient host is a caveat, given the known role of the immune system in tumor progression and response to therapy. Thus, we attempted to develop an immune-humanized PDX model of ER+ MBC. Methods NSG-SGM3 mice were immune-humanized with CD34+ hematopoietic stem cells, followed by engraftment of human ER+ endocrine resistant MBC tumor fragments. Strategies for exogenous estrogen supplementation were compared, and immune-humanization in blood, bone marrow, spleen, and tumors was assessed by flow cytometry and tissue immunostaining. Characterization of the new model includes assessment of the human tumor microenvironment performed by immunostaining. Results We describe the development of an immune-humanized PDX model of estrogen-independent endocrine resistant ER+ MBC. Importantly, our model harbors a naturally occurring ESR1 mutation, and immune-humanization recapitulates the lymphocyte-excluded and myeloid-rich tumor microenvironment of human ER+ breast tumors. Conclusion This model sets the stage for development of other clinically relevant models of human breast cancer and should allow future studies on mechanisms of endocrine resistance and tumor-immune interactions in an immune-humanized in vivo setting.
Databáze: OpenAIRE
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