The OBJECTIVE of this proposal is to investigate the role of soy phytochemicals, dietary constituents with known cancer-preventive properties, in breast cancer metastasis. The RATIONALE is that soy isoflavones can affect cancer progression by antioxidant, estrogenic/antiestrogenic, antiangiogenic, and other inhibitory mechanisms. Most studies on the role of soy compounds in cancer focus on cancer initiation and not progression. This proposal addresses a GAP IN KNOWLEDGE concerning the molecular targets of the major soy isoflavones genistein and dadizein in breast cancer metastasis, the most deadly aspect of the disease. We have shown that the activity of a key signaling intermediate of cancer cell invasion, focal adhesion kinase (FAK), is regulated by genistein and daidzein in metastatic breast cancer cells. Preliminary data using human breast cancer cells in tissue culture and a nude mouse model of experimental metastasis demonstrate that genistein decreases while daidzein increases metastatic breast cancer cell migration, mammary tumor growth, and metastasis. Our HYPOTHESIS is that genistein prevents while daidzein promotes metastatic breast cancer progression. These differential effects are dependent on the myriad of FAK-mediated signaling cascades. The STUDY DESIGN will use innovative in situ image analysis and genomic and proteomic microarray technology to elucidate the FAK signaling pathways that are regulated differentially by soy isoflavones in metastatic breast cancer cell lines that do not express estrogen receptors (ER), only ER beta or both ER isoforms.
AIM 1 will delineate molecular targets of genistein, daidzein, and combined soy isoflavones on metastatic breast cancer cells in vitro.
AIM 2 will delineate molecular targets of genistein, daidzein, and combined soy isoflavones on mammary tumors, distant metastases, and invasive breast cancer cells in vivo. The proposed comprehensive-analysis is expected to identify signaling molecules regulated by soy compounds relevant for breast cancer progression. This timely research is SIGNIFICANT to public health by advancing the understanding of the role of natural dietary compounds from soy foods in breast cancer. The proposed elucidation of the specific molecular targets of soy isoflavones will enable targeted therapeutic strategies for metastatic breast cancer. Our broad-range goal is to impact the development of dietary guidelines for women at risk for breast cancer, breast cancer patients, and survivors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM084824-04
Application #
8133781
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CB))
Program Officer
Krasnewich, Donna M
Project Start
2008-09-10
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$111,375
Indirect Cost
Name
University of Puerto Rico Med Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
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de la Parra, Columba; Castillo-Pichardo, Linette; Cruz-Collazo, Ailed et al. (2016) Soy Isoflavone Genistein-Mediated Downregulation of miR-155 Contributes to the Anticancer Effects of Genistein. Nutr Cancer 68:154-64
de la Parra, Columba; Borrero-Garcia, Luis D; Cruz-Collazo, Ailed et al. (2015) Equol, an isoflavone metabolite, regulates cancer cell viability and protein synthesis initiation via c-Myc and eIF4G. J Biol Chem 290:6047-57
Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba et al. (2014) The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model. Transl Oncol 7:546-55
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Dharmawardhane, Suranganie; Hernandez, Eliud; Vlaar, Cornelis (2013) Development of EHop-016: a small molecule inhibitor of Rac. Enzymes 33 Pt A:117-46
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Castillo-Pichardo, Linette; Dharmawardhane, Suranganie F (2012) Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer. Nutr Cancer 64:1058-69
Montalvo-Ortiz, Brenda L; Castillo-Pichardo, Linette; Hernández, Eliud et al. (2012) Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem 287:13228-38
Martínez-Montemayor, Michelle M; Otero-Franqui, Elisa; Martinez, Joel et al. (2010) Individual and combined soy isoflavones exert differential effects on metastatic cancer progression. Clin Exp Metastasis 27:465-80