The frequency of African American and Latina women diagnosed with HER2-overexpressing breast cancer is higher compared to Caucasians and they are at a higher risk to die from breast cancer. Trastuzumab (Herceptin) has been shown to successfully treat HER2-overexpressing metastatic breast cancer and prolong the survival of patients with HER2-overexpressing breast cancer. However, more than 50% of patients with HER2-overexpressing breast cancer will eventually become resistant to trastuzumab. Preliminary data from our laboratory suggested that up-regulation of Wnt3 (proto-oncogene; ligand for members of the frizzled family) may play a key role toward the development of trastuzumab resistance and metastatic disease in HER2-overexpressing breast cancer. It is interesting to know if inhibition of Wnt signaling could restore the sensitive of trastuzumab and prevent metastases of HER2-overexpressing breast cancer. We hypothesize that Wnt3 associated network of signaling pathways could drive HER2 overexpressing breast tumors to acquire resistance to trastuzumab and increase tumor metastasis. The increased expression of Wnt3 will activate Wnt/?-catenin signaling, promote HER2 cells toward Epithelial to Mesenchymal Transition (EMT), and initiate tumor metastases. Hence, targeting Wnt3 may enhance or restore the HER2 overexpressing breast tumor's response to trastuzumab treatment and consequently inhibit metastasis. To test our hypothesis, we propose three specific aims in this study: (1) Examine the expression of Wnt3 in relation to trastuzumab resistance and tumor metastases in cohort of African American and Latina patients, and the association of Wnt3 with HER family receptors and molecular subtype of breast cancer. We will compare the data obtained from the cohort of African American and Latina with a cohort of samples from Caucasian; (2) Examine the mechanism(s) by which the Wnt3?Wnt/?-catenin pathway initiates and sustains resistance to trastuzumab in HER2-overexpressing breast tumors, and identify the?driver?or ?keymediators? that determine how the HER2-overexprerssing epithelial cells transition to more mesenchymal phenotype and eventually to metastasis; (3) Test inhibition of Wnt3/Wnt ligand in combination with trastuzumab and/or Lapatinib to overcome HER2-cells resistance to trastuzumab and prevent metastases in vitro and in vivo. Activity from the proposed project will provide research education opportunity for students and fellows.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Charles R. Drew University of Medicine & Science
Los Angeles
United States
Zip Code
Boonyaratanakornkit, Viroj; Hamilton, Nalo; Márquez-Garbán, Diana C et al. (2018) Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer. Mol Cell Endocrinol 466:51-72
Chung, Seyung S; Dutta, Pranabananda; Austin, David et al. (2018) Combination of resveratrol and 5-flurouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells. Oncotarget 9:32943-32957
Maxwell, Annette E; Young, Sandra; Moe, Emily et al. (2018) Understanding Factors that Influence Health Care Utilization Among Mixtec and Zapotec Women in a Farmworker Community in California. J Community Health 43:356-365
Maxwell, Annette E; Castillo, Laura; Arce, Anthony A et al. (2018) Eating Veggies Is Fun! An Implementation Pilot Study in Partnership With a YMCA in South Los Angeles. Prev Chronic Dis 15:E132
Elshimali, Yahya I; Wu, Yong; Khaddour, Hussein et al. (2018) Optimization Of Cancer Treatment Through Overcoming Drug Resistance. J Cancer Res Oncobiol 1:
Chung, Seyung S; Adekoya, Debbie; Enenmoh, Ikechukwu et al. (2017) Salinomycin Abolished STAT3 and STAT1 Interactions and Reduced Telomerase Activity in Colorectal Cancer Cells. Anticancer Res 37:445-453
Maxwell, Annette E; Crespi, Catherine M; Arce, Anthony A et al. (2017) Exploring the effects of longstanding academic-community partnerships on study outcomes: A case study. Prev Med Rep 8:101-107
Hamilton, Nalo; Austin, David; Márquez-Garbán, Diana et al. (2017) Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int J Mol Sci 18:
La, V; Fujikawa, R; Janzen, D M et al. (2017) Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy. NPJ Precis Oncol 1:
Wu, Y; Vadgama, J V (2017) Androgen Receptor as a Potential Target for Treatment of Breast Cancer. Int J Cancer Res Mol Mech 3:

Showing the most recent 10 out of 90 publications