A Vascular Restriction of Mammary Tumor Progression

Institution: The Burnham Institute for Medical Research
Investigator(s): Robert Oshima, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6JB-0073 Award: $384,466
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (2000)
The goals of this project are to characterize the influence of pregnancy, lactation and involution on the normal vascular organization of the mammary gland and to determine whether altered levels of the blood vessel growth factors can influence mammary gland susceptibility to tumor growth. It has been known for over twenty years that many cancer cell lines secrete substances that attract blood vessels. Recent progress in our understanding of breast tumor growth and the vascular system suggests that cells surrounding a tumor or even invading blood cells may trigger the signals for new connections to blood vessels. It has been shown in at least two different tumor model systems that when tumor growths reach a certain size they must start attracting new blood vessels or they will fail to continue to grow. We believe this change also must occur in breast cancer and speculate that many of the secondary genetic changes that occur in pre-malignant tumor cells may act to ensure this step. We will test this idea by attempting to make two new transgenic mouse lines that constantly produce blood vessel growth factors (either VEGF or angiopoietin-1). If we can show that the presence of these blood vessel attracting substances speeds up breast tumor progression, we can then dissect the critical steps in the process of blood vessel recruitment. In addition, we speculate that blood vessel remodeling must occur after lactation. It remains to be determined if the vascularity of the resting mammary gland is different after lactation. Such a difference may contribute to the decrease in cancer risk associated with having children.

Final Report (2002)
We identified 14 VEGF (vascular endothelial growth factor) transgenic mouse lines and eventually concentrated on three lines for our studies. We found that very high levels of VEGF resulted in male sterility and female lactation defects. However, progeny could be rescued by foster mothers. Lower levels of VEGF expression resulted in acceptable transmission and permitted the evaluation of the impact of VEGF on mammary tumor appearance by mating the mice with another strain that carrying an activated ErbB2/Neu gene that causes tumors in about 110 days.

We found that VEGF expression dramatically accelerated tumor formation to about 50 days. Indeed soon after mammary gland development began, hyperplastic mammary epithelial tissues began developing as tumors. This acceleration was accompanied by increased vascularity of the tumors. In contrast to tumor formation, normal mammary gland development in these mice was not distinguishable from control mice in spite of high levels of VEGF RNA and protein. This suggests that other compensatory mechanisms are available to moderate blood vessel development during normal mammary gland development in the face of elevated, cell associated VEGF expression. However, oncogenic stimulation of mammary epithelial cells is apparently not subject to these moderating influences.

The most surprising result of our experiments is the tremendous acceleration of the rate of progression of cells to tumors. New vessel development was expected to be important for relatively large tumors. However, our results indicate that an increased blood supply may be the most critical step for causing proliferating cells to advance to even small tumors. Our results are currently in the final stages of preparation for publication.

Angiogenic acceleration of Neu induced mammary tumor progression and metastasis.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Oshima RG, et al Muller WJ, Hauser CA, Cardiff RD
Yr: 2004 Vol: 64 Nbr: 1 Abs: Pg:169-79