Abstract
Previous studies based on cell culture and xenograft animal models suggest that Smad3 has tumor suppressor function for breast cancer during early stages of tumorigenesis. In this report, we show that DMBA (7,12-dimethylbenz[a]anthracene), a chemical carcinogen, induces mammary tumor formation at a significantly higher frequency in the Smad3 heterozygous mice than in the Smad3 wild type mice. This is the first genetic evidence showing that Smad3 inhibits mammary tumor formation in a mouse model. Our findings support the notion that Smad3 has important tumor suppressor function for breast cancer.
Highlights
TGF-ß/Smad3 upregulates the expression of a set of genes including Ephrin-A1, which is shown to contribute to the TGF-ß/Smad3 tumor suppressive effects in ER-positive breast cancer [6]
We show in this study that DMBA-induced mammary tumor formation is accelerated in the Smad3+/- mice compared to the Smad3+/+ mice
Tumor formation was monitored for six months after beginning DMBA
Summary
Smad3-/- mice cannot be used for analysis of spontaneous mammary tumor formation, as they do not survive beyond at most 8 months due to certain defects [13, 17, 18]. The Smad3+/- (heterozygous) mice do not form spontaneous mammary tumors (data not shown). Previous xenograft experiments showing Smad3 tumor suppressor function for breast cancer used the MCF10CA1h cell line [6, 8], which contains an oncogenic H-Ras mutation.
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