A novel and cost-effective ex vivo orthotopic model for the study of human breast cancer in mouse mammary gland organ culture

Author:

Gupta Akash1,Gupta Geetanjali1,Mehta Rajeshwari R.2,Ivancic David Z.3,Walker Rashidra R.4,Patel Jankiben R.4,Gallegos Karen M.4,Davidson A. Michael4,Khan Seema A.3,Mehta Rajendra G.2,Tilghman Syreeta L.4ORCID

Affiliation:

1. Department of Medicine, University of Arizona, Tucson, AZ, USA

2. IIT Research Institute, Chicago, IL, USA

3. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

4. Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA

Abstract

Mouse Mammary Organ Culture (MMOC) is used to evaluate the efficacy of chemopreventive agents against the development of carcinogen-induced preneoplastic lesions and is highly correlative to in vivo carcinogenesis models. Here, we developed a new ex vivo MMOC model, by introducing human breast cancer cells into the mouse mammary gland. This novel model, termed human Breast Cancer in MMOC (BCa-MMOC), mimics in vivo orthotopic breast cancer mouse models. To develop this model, estradiol- and progesterone- sensitized female mice were injected with letrozole sensitive- and resistant T47D breast cancer cells in the mammary glands and then sacrificed. The glands were cultured in vitro with hormone-supplemented media. On day 25, the glands were fixed and processed by histopathology and immunohistochemistry to evaluate for the presence of T47D cells, growth pattern, cancer markers, and estradiol responsiveness. Histopathological analyses demonstrated an identical pattern of growth between the breast cancer cells injected ex vivo and in vivo. Interestingly, clusters of cancer cells in the mammary gland stroma appeared similar to those observed in human breast tumors. The injected T47D cells survived and proliferated for 15 days maintaining expression of ER, PR, EGFR, and aromatase. The aromatase-overexpressing T47D grown in the BCa-MMOC sufficiently metabolized estrogen, resulting in enhanced cell proliferation, induction of estrogen target genes (i.e. ER and PR-B), and showed typical changes to estrogenic milieu. In summary, here we show a novel, inexpensive ex vivo model, to potentially study the effects of therapeutic agents on cancer cells grown in an orthotopic micromilieu.

Funder

National Institutes of Health

Publisher

The Company of Biologists

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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