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IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways
Tania Benatar1, Wenyi Yang, Yutaka Amemiya
1Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, ON, Canada.
Abstract:
Insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be a tumor suppressor in a variety of cancers. We previously have shown that IGFBP7 expression is inversely correlated with disease progression and poor outcome in breast cancer. Overexpression of IGFBP7 in MDA-MB-468, a triple-negative breast cancer (TNBC) cell line, resulted in inhibition of growth and migration. Xenografted tumors bearing ectopic IGFBP7 expression were significantly growth-impaired compared to IGFBP7-negative controls, which suggested that IGFBP7 treatment could inhibit breast cancer cell growth. To confirm this notion, 14 human patient primary breast tumors were analyzed by qRTPCR for IGFBP7 expression. The TNBC tumors expressed the lowest levels of IGFBP7 expression, which also correlated with higher tumorigenicity in mice. Furthermore, when breast cancer cell lines were treated with IGFBP7, only the TNBC cell lines were growth inhibited. Treatment of NOD/SCID mice harboring xenografts of TNBC cells with IGFBP7 systemically every 3-4 days inhibited tumorigenesis, with associated anti-angiogenic effects, together with increased apoptosis. Upon examining the mechanism of IGFBP7-mediated growth inhibition in TNBC cells, we found that cells not only were arrested in G1 phase of the cell cycle but also underwent senescence as a result of treatment with IGFBP7. Interestingly, IGFBP7 treatment was also associated with strong activation of the stress-associated p38 MAPK pathway, together with upregulation of p53 and the cyclin-dependent protein kinase (CDK) inhibitor, p21(cip1). Prolonged treatment of cells with IGFBP7 resulted in increased cell death, marked by an increase in apoptotic cells and associated cleaved PARP. This is the first study showing that exogenous IGFBP7 inhibits TNBC cell growth both in vitro and in vivo. Taken together, these results suggest IGFBP7 treatment might have therapeutic potential for TNBC.
Insights
Insulin-like growth factor binding protein 7 (IGFBP7) inhibits triple-negative breast cancer (TNBC) growth by inducing cell cycle arrest and senescence. This study suggests IGFBP7 as a potential therapeutic for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Insulin-like growth factor binding protein 7 (IGFBP7) acts as a tumor suppressor in various cancers.
- Previous research indicates IGFBP7 expression inversely correlates with disease progression and poor outcomes in breast cancer.
- IGFBP7 overexpression inhibits growth and migration in MDA-MB-468, a triple-negative breast cancer (TNBC) cell line.
Purpose of the Study:
- To investigate the therapeutic potential of IGFBP7 in inhibiting breast cancer cell growth, particularly in TNBC.
- To analyze IGFBP7 expression levels in human breast tumors and correlate them with tumorigenicity.
- To elucidate the mechanisms underlying IGFBP7-mediated growth inhibition in TNBC cells.
Main Methods:
- Quantitative reverse transcription PCR (qRT-PCR) to analyze IGFBP7 expression in 14 primary breast tumors.
- In vitro treatment of breast cancer cell lines with IGFBP7.
- In vivo studies using NOD/SCID mice xenografted with TNBC cells and treated systemically with IGFBP7.
- Cell cycle analysis, senescence assays, Western blotting for pathway activation (p38 MAPK, p53, p21(cip1)), and apoptosis assays (cleaved PARP).
Main Results:
- TNBC tumors exhibited the lowest IGFBP7 expression, correlating with higher tumorigenicity.
- Exogenous IGFBP7 inhibited the growth of TNBC cell lines in vitro and significantly impaired xenograft tumor growth in vivo.
- IGFBP7 treatment induced G1 cell cycle arrest, senescence, activated the p38 MAPK pathway, upregulated p53 and p21(cip1), and promoted apoptosis in TNBC cells.
- Systemic IGFBP7 treatment in mice showed anti-angiogenic effects and increased tumor cell apoptosis.
Conclusions:
- Exogenous IGFBP7 demonstrates significant inhibitory effects on triple-negative breast cancer cell growth both in vitro and in vivo.
- IGFBP7 treatment induces cell cycle arrest, senescence, and apoptosis, mediated by the p38 MAPK pathway, p53, and p21(cip1).
- These findings highlight IGFBP7 as a promising therapeutic candidate for triple-negative breast cancer.
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