Abstract
ABSTRACTMouse 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 euthanized. 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 estrogen receptor alpha (ER), progesterone receptor (PR), epidermal growth factor receptor (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.This article has an associated First Person interview with the first author of the paper.
Highlights
Mammary glands undergo morphological and biochemical changes during various physiological stages of life, during the transition through nulliparity, pregnancy, lactation, and involution (Guzman et al, 1999, Medina, 1996, Nandi et al, 1995)
Estradiol- and progesterone- sensitized female mice were injected with letrozole sensitive- and resistant T47D breast cancer cells in the mammary glands and sacrificed
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
Summary
Mammary glands undergo morphological and biochemical changes during various physiological stages of life, during the transition through nulliparity, pregnancy, lactation, and involution (Guzman et al, 1999, Medina, 1996, Nandi et al, 1995). Mehta and colleagues have successfully used the MMOC model to screen various chemopreventive agents for the past two decades and have demonstrated that this model is relevant, reliable and inexpensive (Mehta et al, 2008) Using this model, the chemopreventive efficacy of various chemical or naturally isolated agents were evaluated based on their potential to suppress hyperplastic, mammary ductal or lobular alveolar lesions induced in the presence of various hormonal milieu (aldosterone or estradiol or progesterone) following exposure to chemical carcinogens such as Dimethylbenz(a)anthracene (DMBA) (Mehta et al, 2001). The MMOC model has great translational implications to predict the potential efficacy of promising anti-cancer drugs Selection of such agents could lead to future pre-clinical testing or clinical trials. While the MMOC model has certain drawbacks, such as the inability to explore bioavailability or metabolism of experimental drugs, it is a cost effective and reliable model to pre-screen new chemopreventive agents for breast cancer
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