Death from prostate cancer (PCa) is caused by the metastatic dissemination of PCa cells from the prostate gland. Dietary consumption of genistein is associated with a lower incidence metastatic PCa. In preclinical models genistein inhibits PCa cell motility and metastasis at concentrations linked to dietary consumption. In a prospectively designed clinical trial, genistein exerts antimotility efficacy on prostate cells in man. We hypothesize that genistein therapeutically modulates signaling pathways in man that regulate PCa cell motility. We have elucidated two signaling pathways by which human PCa cells regulate motility: (1) the heat shock protein 27 (HSP27) pro-motility pathway-inhibited by genistein. (2) the endoglin anti-motility pathway-activated by genistein. In animals, genistein inhibits human PCa metastasis. In phase 1 and phase 2 trials in men with PCa, genistein is well tolerated, inhibits prostate cell detachment, and selectively modulates genes which regulate PCa cell motility. We propose three Aims designed to increase our understanding of how PCa cells regulate motility, of how genistein modulates those regulatory pathways, and of genistein's effect in man.
Aim 1 Elucidate the mechanisms by which endoglin (a TGF2 superfamily accessory receptor) regulates PCa cell motility, and determine their role in mediating genistein's efficacy. Studies will identify which TGF2 type II receptor subtype is necessary for endoglin signaling. They will also determine whether endoglin mediates cell motility by binding to integrin adhesion molecules. Genistein's dependence upon each of these mechanisms will be evaluated.
Aim 2 Determine whether HSP27 inhibits genistein efficacy by modifying actin function. The role of HSP27-actin interaction in regulating cell adhesion and invasion, and genistein efficacy, will be determined. As HSP27 is up regulated during PCa progression in man, murine studies will assess whether HSP27 regulates PCa metastatic behavior, and how its expression affects genistein antimetastatic efficacy.
Aim 3 Assess if genistein alters molecular pathways in man which regulate prostate cell motility. Using banked prostate tissue from our phase 2 trial, investigations will determine whether genistein exerts therapeutically relevant anti-motility effects at the molecular level in man. Studies performed upon human tissue will be dictated, in part, by investigations performed in Aims 1 and 2. Prostate cancer causes death by moving throughout the body, thereby forming metastasis.

Public Health Relevance

Genistein is a chemical in soy that inhibits metastasis in animals. We have shown that in man, genistein appears to stop prostate cells from moving. This proposal seeks to find out how genistein is working in man. This information is necessary in order be able to use genistein to effectively inhibit prostate cancer metastasis in man.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Adams, Daniel L; Martin, Stuart S; Alpaugh, R Katherine et al. (2014) Circulating giant macrophages as a potential biomarker of solid tumors. Proc Natl Acad Sci U S A 111:3514-9
Pavese, Janet M; Ogden, Irene M; Voll, Eric A et al. (2014) Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis. PLoS One 9:e102289
Voll, Eric A; Ogden, Irene M; Pavese, Janet M et al. (2014) Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression. Oncotarget 5:2648-63
Krishna, Sankar N; Bergan, Raymond C (2014) Therapeutic modulation of prostate cancer metastasis. Future Med Chem 6:223-39
Pavese, Janet M; Bergan, Raymond C (2014) Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. Cancer Lett 352:179-86
Pavese, Janet; Ogden, Irene M; Bergan, Raymond C (2013) An orthotopic murine model of human prostate cancer metastasis. J Vis Exp :e50873
Breen, Michael J; Moran, Diarmuid M; Liu, Wenzhe et al. (2013) Endoglin-mediated suppression of prostate cancer invasion is regulated by activin and bone morphogenetic protein type II receptors. PLoS One 8:e72407
Xu, Li; Wang, Sophia S; Healey, Megan A et al. (2011) The Ninth Annual American Association of cancer research international conference on frontiers in cancer prevention research. Cancer Prev Res (Phila) 4:616-21
Lakshman, Minalini; Huang, Xiaoke; Ananthanarayanan, Vijayalakshmi et al. (2011) Endoglin suppresses human prostate cancer metastasis. Clin Exp Metastasis 28:39-53
Romero, Diana; O'Neill, Christine; Terzic, Aleksandra et al. (2011) Endoglin regulates cancer-stromal cell interactions in prostate tumors. Cancer Res 71:3482-93

Showing the most recent 10 out of 12 publications