Abstract
BackgroundOsteopontin is a secreted phosphoglycoprotein that is expressed by a number of normal cells as well as a variety of tumor cells. With respect to breast cancer, osteopontin has been implicated in regulating tumor cell proliferation and migration/metastasis and may serve as a prognostic indicator. However it remains unclear whether osteopontin has the same impact in all breast cancer subtypes and in particular, osteopontin’s effects in claudin-low breast cancer are poorly understood.MethodscDNA microarrays and qRT-PCR were used to evaluate osteopontin expression in mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors. siRNA was then used to determine the impact of osteopontin knockdown on proliferation, apoptosis and migration in vitro in two murine claudin-low cell lines as well as identify the receptor mediating osteopontin’s physiologic effects.ResultsOsteopontin was expressed at high levels in mammary tumors derived from MTB-IGFIR transgenic mice compared to normal mammary tissue. Evaluation of cell lines derived from different mammary tumors revealed that mammary tumor cells with claudin-low characteristic expressed high levels of osteopontin whereas mammary tumor cells with mixed luminal and basal-like features expressed lower levels of osteopontin. Reduction of osteopontin levels using siRNA significantly reduced proliferation and migration while increasing apoptosis in the claudin-low cell lines. Osteopontin’s effect appear to be mediated through a receptor containing ITGAV and not through CD44.ConclusionsOur data suggests that mammary tumors with a mixed luminal/basal-like phenotype express high levels of osteopontin however this osteopontin appears to be largely produced by non-tumor cells in the tumor microenvironment. In contrast tumor cells with claudin-low characteristics express high levels of osteopontin and a reduction of osteopontin in these cells impaired proliferation, survival and migration.
Highlights
Osteopontin is a secreted phosphoglycoprotein that is expressed by a number of normal cells as well as a variety of tumor cells
primary mammary tumors (PMT) were induced by the transgenic expression of the type I insulin-like growth factor receptor (IGF-IR) in mammary epithelial cells of MTB-IGFIR transgenic mice while recurrent spindle tumors (RST) resulted following the downregulation of the IGF-IR transgene in PMTs
Since the most differentially expressed gene between normal mouse mammary tissue and IGF-IR induced mammary tumors identified in our previous study was gene name for osteopontin (Spp1), this gene was further examined in this current manuscript in the transgenic model and cell lines derived from the IGF-IR transgenic mice (MTB-IGFIR transgenic mice)
Summary
Osteopontin is a secreted phosphoglycoprotein that is expressed by a number of normal cells as well as a variety of tumor cells. With respect to breast cancer, osteopontin has been implicated in regulating tumor cell proliferation and migration/metastasis and may serve as a prognostic indicator. It remains unclear whether osteopontin has the same impact in all breast cancer subtypes and in particular, osteopontin’s effects in claudin-low breast cancer are poorly understood. Osteopontin (OPN, Spp1) is a secreted glycophosphoprotein expressed by a number of cell types including endothelial cells, vascular smooth muscle cells, neural cells, epithelial cells, osteoblasts/osteoclasts, and immune cells [1,2,3].
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