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Novel Anti-angiogenic Therapies Using Naturally Occurring and Synthetic Drugs to Combat Progestin-Dependent Breast Cancer

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Cell and Molecular Biology of Breast Cancer

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Abstract

Angiogenesis, the process by which new blood vessels are formed, is essential for both normal and pathological tissue expansion and provides the nourishment necessary for growth. The role of growth factors which promote angiogenesis in pathologic conditions of the breast is now well established. Recently the synthetic progestin component of combination estrogen and progestin hormone replacement therapy (HRT) has been associated with increased risk of breast cancer in postmenopausal women. We demonstrated that progestins induce breast cancer cells to produce vascular endothelial growth factor (VEGF), a potent angiogenic growth factor that promotes angiogenesis and causes tumors to grow. Unfortunately, synthetic antiprogestins are toxic, precluding their use as a means by which to suppress the proangiogenic activity of administered progestins. In this chapter we will discuss our studies aimed at identifying both naturally occurring and synthetic compounds with antiprogestin and anti-angiogenic activities. We will describe our progress using agents which block the production of progestin-induced VEGF from breast cancer cells and which also have the capacity to both treat and prevent progestin-dependent breast disease in animal models. We contend that information gained from such studies could facilitate the development of personalized medicine which might be used to more precisely and selectively target a specific signal transduction pathway essential to angiogenesis, thereby controlling the formation of new blood vessels essential for nourishing the rapid growth of hormone-dependent breast tumors. Our studies could also further the concept of “angio-prevention” of breast cancer in individuals who are particularly susceptible to progestin-dependent disease, for example, women who have mutations in tumor suppressors such as p53 and Brca-1. By maintaining the angiogenic switch “off” within tumor cells, the development of hormone-dependent breast cancers may be prevented.

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Acknowledgments

We are grateful to the talented individuals in the lab, both past and present, who have been instrumental in obtaining the exciting data reported herein. These include Drs. Yayun Liang, Indira Benakanakere, Candace Carroll, and Jianbo Wu. We are also grateful to various collaborators for their contribution, in particular Dr. George Stancel (Univ. of Texas, Houston), in whose laboratory SMH began his research on hormones and angiogenesis, and Drs. Rolf Brekken and Philip Thorpe (UT Southwestern, Dallas, TX) who provided the anti-vascular antibodies for use in these studies. We also wish to thank the lab staff at RADIL/IDDEX for help with the immunohistochemical analysis.

Funding

The following sources are acknowledged for supporting our laboratory studies: NIH grants CA-86916 and R56-CA86916, the Susan G. Komen Breast Cancer Foundation, Dept of Defense breast cancer awards (W81XWH-05-1-0416, W81XWH-06-1-0646 and W81XWH-12-1-0191), and COR grants from the College of Veterinary Medicine at the University of Missouri, Columbia. SMH is the Zalk Missouri Professor of Tumor Angiogenesis. Mrs. Zalk’s bequest has been instrumental in allowing us to make key discoveries related to the role of progestins and angiogenic growth factors in breast cancer. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Authors and Affiliations

  1. Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, MO, 65211, USA

    Salman M. Hyder & Benford Mafuvadze

  2. IDEXX RADIL, Columbia, MO, 65201, USA

    Cynthia Besch-Williford

Authors
  1. Salman M. Hyder
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  2. Benford Mafuvadze
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  3. Cynthia Besch-Williford
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Corresponding author

Correspondence to Salman M. Hyder .

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Editors and Affiliations

  1. University of Missouri-Columbia Dept. Veterinary Pathobiology, Columbia, Missouri, USA

    Heide Schatten

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Hyder, S.M., Mafuvadze, B., Besch-Williford, C. (2013). Novel Anti-angiogenic Therapies Using Naturally Occurring and Synthetic Drugs to Combat Progestin-Dependent Breast Cancer. In: Schatten, H. (eds) Cell and Molecular Biology of Breast Cancer. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-634-4_7

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