Triple negative (TN) invasive breast carcinomas comprise 10% of breast cancers but result in a large number of deaths, especially among African American women. Characterizing genes that drive these tumors'rapid progression may identify novel biomarkers to guide current treatments, may offer novel therapeutic targets, and decrease health disparities. Although the cellular origin of TN carcinomas is ijnknown, recent studies strongly suggest that they derive from luminal progenitor cells. We have identified EZH2 as a critical oncogene specifically upregulated in ER negative carcinomas and their metastasis when compared to normal breast tissues. EZH2 expression increases during tumorigenesis and is significantly associated with poor clinical outcome. Of note, EZH2 downregulation in TN breast cancer cell lines decreased their growth in vivo and improved survival. We recently discovered that EZH2 overexpression expands the tumorigenic stem cell population with a specific increase in the number of luminal progenitors in a Notchi-depedent manner. Our Central Hypothesis is that dysregulated expression of EZH2 promotes TN breast carcinogenesis by increasing the breast stem cell population, particularly the luminal progenitors. We further hypothesize that EZH2 expression and detection of luminal progenitors may be novel biomarkers of metastasis and prognosis in TN invasive carcinomas from Caucasian, African American, and West African women.
Our aims are:
Aim 1. To elucidate the role of EZH2 in the maintenance of stem cells and luminal progenitors that give rise to TN invasive carcinomas;
and Aim 2. To assess the clinical utility of EZH2 overexpression and detection of luminal progenitors as biomarkers of survival in TN invasive carcinomas from Caucasian, African American, and West African women . This proposal combines the use of unique, well-annotated human tissues from Caucasian, African-American, and West-African patients from Ghana with in vivo and in vitro models of TN breast carcinoma. Our goal is that the functional characterization of EZH2 in TN breast cancer will identify a new pathway driving these aggressive tumors, and allow tailored treatment and perhaps targeted intervention to prevent the development of metastases.
Triple negative (estrogen, progesterone, and HER2 negative) invasive breast carcinomas comprise 10% of all breast cancers but have increased incidence and mortality in African American women. This study will elucidate how EZH2 regulates the development of triple negative breast cancer and the clinical utility of EZH2 and luminal progenitor cells as biomarkers of survival according to racial groups.
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