Abstract
Non-acute transforming retroviruses like mouse mammary tumor virus (MMTV) cause cancer, at least in part, through integration near cellular genes involved in growth control, thereby de-regulating their expression. It is well-established that MMTV commonly integrates near and activates expression of members of the Wnt and Fgf pathways in mammary tumors. However, there are a significant number of tumors for which the proviral integration sites have not been identified. Here, we used high through-put screening to identify common integration sites (CISs) in MMTV-induced tumors from C3H/HeN and BALB/c mice. As expected, members of both the Wnt and Fgf families were identified in this screen. In addition, a number of novel CISs were found, including Tcf7l2, Antxr1/Tem8, and Arhgap18. We show here that expression of these three putative oncogenes in normal murine mammary gland cells altered their growth kinetics and caused their morphological transformation when grown in three dimensional cultures. Additionally, expression of Tcf7l2 and Antxr1/Tem8 sensitized cells to exogenous WNT ligand. As Tcf7l2, Antxr1/Tem8, and Arhgap18 have been associated with human breast and other cancers, these data demonstrate that MMTV-induced insertional mutation remains an important means for identifying genes involved in breast cancer.
Highlights
mammary tumor virus (MMTV)-induced mammary tumorigenesis in mice has long been used as a model for the study of human breast cancer
The tumors were derived from C3H/HeN mice infected with MMTV(C3H) and BALB/c mice infected with MMTV(HP) or MMTV(Y1Y2) [15], all of which acquired the virus neonatally through milk-borne transmission
Included in the major advances made in breast cancer research was the finding that MMTV induced mammary tumors through the action of virus-encoded transcriptional regulatory elements that activate cellular oncogene expression after proviral integration [27]
Summary
MMTV-induced mammary tumorigenesis in mice has long been used as a model for the study of human breast cancer. A number of groups have used high throughput analysis to identify retroviral integration sites in murine leukemia virus (MLV)-transduced cells and after MLV and MMTV proviral, as well as retrotransposon insertion in tumors as a means of identifying novel oncogenes [2,4,8,9,10,11,12]. Many of these studies have been compiled into a database termed the RetrovirusTagged Cancer Gene Database (RTCGD) [13]. Most of the novel hits deposited in the RTCGD have not been validated in biological assays
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