A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease

Abstract

BackgroundTriple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems.MethodsTo understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis.ResultsWe isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A).ConclusionsTaken together, we have developed a TNBC-TICs model system based on the 4T1 cells which is a very useful metastasis model with the advantage of being able to be transplanted into immune competent recipients. Our data demonstrates that the TNBC-TICs model system could be a useful tool for studies on the pathogenesis and therapeutic treatment for TNBC.

Brazilein in Combination with Cisplatin Inhibit Proliferation and Migration on Highly Metastatic Cancer Cells, 4T1

“…In this report, we present the effect of brazilein on several physiological targets on cancer development, especially on metastatic breast cancer cells. We used 4T1 cells line that has been recognized as active cells in proliferation and migration (Kaur et al, 2012). Comprehensively, we found that brazilein exhibited middle or low cytotoxic effect, cell cycle modulation, apoptosis induction, and inhibition of cells migration.…”

“…On the other hand, cancer progression usually involve aberration of cell proliferation and cell migration as well as invasion (Kemper et al, 2014). The 4T1 cell is the example of metastatic breast cancer that *Corresponding author: Riris Istighfari Jenie Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia, 55281 Email: riris_jenie@ugm.ac.id (Laksmiani et al, 2015) performs active proliferation, migration and invasion (Kaur et al, 2012). Some growth signaling involve in the 4T1 cells proliferation including activation of NFκB transcription factor (Tsubaki et al, 2013).…”

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…It has been documented that, these cells have a considerable subpopulation of CSC that confer proven IR resistance [92,101,[107][108][109][110][111]. These characteristics make these cells a reliable candidate to compare their IR biological response to that of aMSCs.…”

Lx2-32c–loaded polymeric micelles with small size for intravenous drug delivery and their inhibitory effect on tumor growth and metastasis in clinically associated 4T1 murine breast cancer

“…We know that spontaneous metastasis usually occurs in late stages of cancer, and 4T1, a representative of metastasis, primarily metastasizes to the lung. 11 Likewise, ex vivo imaging ( Figure 8C) revealed that bioluminescence signal could be detected in the lung (yellow arrow) of control group, which revealed that many tumor cells were most likely to metastasize to lungs. In order to confirm this, we dissected lung tissues from mice and fixed them with Bouin's solution to observe tumor metastasis to lungs.…”

“…The 4T1 mouse mammary tumor cell line is one of only a few breast cancer models having the capacity to metastasize efficiently to sites similar to human breast cancer when implanted orthotopically, and it is also a late stage breast cancer. 11,12 So, 4T1 cells were selected as the model system in the present study. Considering that there is no commercialized product of Lx2-32c, we employed Cremophor EL and ethanol (v/v =1:1) as the solvent to obtain Lx2-32c solution, referred to as Taxol ® , in this study.…”