Mouse mammary tumor virus sequences responsible for activating cellular oncogenes

Area of Science:

• * Molecular biology
• * Cancer research
• * Virology

Background:

• * Mouse mammary tumor virus (MMTV) integration near proto-oncogenes like int-2 can lead to mammary adenocarcinomas.
• * MMTV provirus integration is often in a transcriptional orientation opposite to the target proto-oncogenes.

Purpose of the Study:

• * To investigate the mechanism by which MMTV integration activates cellular proto-oncogenes.
• * To identify specific elements within the MMTV long terminal repeat (LTR) responsible for activating the int-2 promoter.

Main Methods:

• * Development of a novel vector-based system to mimic MMTV integration upstream of the int-2 promoter.
• * Comparative analysis of promoter activation by MMTV LTR versus cellular or other retroviral promoters.
• * Mapping of MMTV LTR sequences responsible for enhancing int-2 promoter activity.

Main Results:

• * The MMTV LTR, when integrated upstream of int-2, is highly effective at activating the int-2 promoter, surpassing other promoters.
• * Two distinct domains within the 5' end of the MMTV LTR were identified as crucial for enhancing int-2 promoter activity.
• * These activating elements exhibit mammary cell-specific activity and act synergistically.
• * Hormonal stimulation of the MMTV promoter only modestly increased int-2 transcription, indicating the primary role of LTR elements.

Conclusions:

• * Viral integration can position MMTV LTR elements to efficiently activate transcription of cellular proto-oncogenes.
• * The 5' elements of the MMTV LTR are the primary drivers of tissue- and orientation-specific activation of cellular promoters.
• * These findings elucidate a key mechanism in MMTV-induced mammary tumorigenesis.