Breast cancer is the most commonly diagnosed cancer in US women. Notably, premenopausal African- American women have a significantly higher incidence rate of breast cancer compared to Caucasian- American, and a higher mortality rate at any age. Reports show young African-American patients have a higher incidence of the basal-like """"""""triple-negative"""""""" breast cancer. Currently, no effective molecular therapies exist for this highly aggressive cancer and, consequently, patient survival is poor. The primary significance of the proposed study is its focus on identifying and testing novel translational targets for treatment of this aggressive, basal-like breast cancer. Previous studies show high CD44 expression is a critical component of stem-like, xenograft-initiating cells in basal-like breast cancer;therefore, defining the role of CD44 in these tumor-initiating cells is a essential step in developing targeted therapeutics. Preliminary results show an upregulation of CD44, and unique CD44 variant expression, in basal-like breast cancer compared to luminal breast cancer subtypes. Additionally, preliminary studies have identified a novel exotoxin, commonly associated with enteric diseases of mammals, that selectively binds high CD44 expressing breast cancer cells, alters CD44 signaling and induces cell death. Therefore, this proposal intends to functionally determine the mechanisms of this toxin's interaction with CD44 and to determine its potential as a therapy for high CD44 expressing, basal-like breast cancer. During the first phase of this proposal, the total levels and variant expression profile of CD44 wil be defined in luminal and basal-like breast cancer phenotypes using absolute quantitative RT-PCR, flow cytometry and immunohistochemistry in cell lines and primary breast cancer samples. This information will be used to define the toxin's target population of cells, and correlate the sensitivity of cancer cells to toxin exposure with CD44 expression and cancer phenotypes (Aim 1). The second phase of this study proposes the initial in vivo xenograft experiments necessary for translational development of the toxin for cancer therapeutics (Aim 2). The data generated from this proposal will provide the foundation of future proposals with the overall goal to develop novel targeted therapies for treatment of aggressive, basal-like breast cancer, particularly in young African-American women.
Premenopausal African-American women suffer disproportionately from a highly aggressive form of breast cancer and, therefore, survival is poor. This proposal focuses on the development and testing of a novel targeted therapeutic for the treatment of this type of breast carcinoma that predominately affects these women.
|Reaves, Denise K; Hoadley, Katherine A; Fagan-Solis, Katerina D et al. (2017) Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis. Mol Cancer Res 15:165-178|
|Reaves, Denise K; Ginsburg, Erika; Bang, John J et al. (2015) Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion? Endocr Relat Cancer 22:R69-86|
|D'Arcy, Monica; Fleming, Jodie; Robinson, Whitney R et al. (2015) Race-associated biological differences among Luminal A breast tumors. Breast Cancer Res Treat 152:437-48|
|Fagan-Solis, Katerina D; Reaves, Denise K; Rangel, M Cristina et al. (2014) Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer. Mol Cancer 13:163|
|Stiles, Bradley G; Pradhan, Kisha; Fleming, Jodie M et al. (2014) Clostridium and bacillus binary enterotoxins: bad for the bowels, and eukaryotic being. Toxins (Basel) 6:2626-56|
|Reaves, Denise K; Fagan-Solis, Katerina D; Dunphy, Karen et al. (2014) The role of lipolysis stimulated lipoprotein receptor in breast cancer and directing breast cancer cell behavior. PLoS One 9:e91747|
|Casbas-Hernandez, Patricia; D'Arcy, Monica; Roman-Perez, Erick et al. (2013) Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Breast Cancer Res 15:R82|
|Fleming, Jodie M; Ginsburg, Erika; Goldhar, Anita S et al. (2012) Progesterone receptor activates Msx2 expression by downregulating TNAP/Akp2 and activating the Bmp pathway in EpH4 mouse mammary epithelial cells. PLoS One 7:e34058|