Targeting IGF2 and Androgen Receptors for TNBC Therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer: Among women, receiving a diagnosis of breast cancer (BC) raises serious concerns regarding prognosis and survival. Indeed, certain types of BC are more-well studied and successfully treated than others. Specifically, unlike women with estrogen receptor-? (ER?) positive BC whose survival outcomes can be positively impacted by successful endocrine therapy, women with triple-negative breast cancer (TNBC) have not benefited from these advances. Women with TNBC cannot be treated with current endocrine therapies and though initially responsive to chemotherapy, frequently women with TNBC have early relapse and metastasis. Thus, women with TNBC continue to account for almost half of all breast cancer deaths. This disparity is concerning because those most often diagnosed with TNBC are women in their reproductive years and/or women who are African American. In light of this, our research priority is to identify prognostic/therapeutic targets that can be used to develop more effective treatments for women with TNBC. 
 
 
 
 The question(s) or central hypotheses of the research: Our central hypothesis is: In TNBC the insulin-like growth factor – 2 (IGF2) signaling cascade plays a significant role in TNBC proliferation and metastasis. Within this signaling pathway several potential therapeutic targets exist. One is IGF2, itself, a metabolic factor that is highly expressed in TNBC. IGF2 mediates its effects through the insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), both of which are potential targets for TNBC treatment. Additionally there is the androgen receptor (AR), a member of the steroid receptor family. Like IGF2, AR is highly expressed in TNBC and associated with TNBC progression. We have also learned that there is communication between the signaling pathways of IGF2 and AR. Because of our research and the state of the current scientific literature, we expect that IGF2 and AR are potential biomarkers for the development of TNBC. One way to test our central hypothesis is to screen a large cadre of TNBC samples to assess their predictive value of TNBC. Another is targeting one or more targets in the IGFR signaling pathway to determine their therapeutic potential for women with TNBC. 
 
 
 
 The general methodology: Our first aim will help us investigate the clinical correlation of IGF2 and AR with TNBC. Using a tissue microarray (TMA) consisting of &gt;250 TNBC cases from African American, Caucasian and Latina women we will be able to assess expression of IGF2 and AR as well as their clinical correlation to TNBC outcomes among a diverse racial/ethnic patient population. In this way we will be able to highlight potential biological targets for TNBC disparity and develop a rationale for TNBC screening assays. Our second aim will allow us to assess the anti-tumor effects of IGF1R/IR and AR antagonists. Using laboratory methods we will inhibit the action of IGF1R/IR and AR targets while assessing cell growth, migration and invasion. Using mice we will be able to assess the therapeutic potential of IGF1R/IR and AR antagonists and their ability to reduce tumor growth and metastasis in a more native environment. The ability to demonstrate anti-cancer activity in TNBC will promote the use of anti-TNBC agents in future clinical trials. 
 
 
 
 Innovative elements of the project and potential impact: Currently no specific treatments for TNBC exist. Thus, the identification of new therapeutic targets for clinical-translation is very significant and imperative. Investigating the role and interactions of IGF2 and AR in TNBC growth and metastasis is a novel research paradigm. Increased expression of IGF2 and AR have been shown to significantly associate with TNBC progression. Thus investigating the correlation between IGF2 and AR in African American women (and men) and others from diverse racially/ethnic backgrounds diagnosed with TNBC will potentially help to improve diagnosis and/or prognosis of TNBC. Assessing the anti-cancer effects of AR, IGF1R and IR antagonists could ultimately improve therapeutic options and the long-term survival of those afflicted with TNBC. Hence, this evidence-based investigation of IGF2 and AR and their molecular interactions may significantly change our approach to TNBC management.