Dissertation Defense: Francisco Saenz
Candidate Name: Francisco Rodolfo Sáenz
Major: Tumor Biology
Advisor: Anna T. Riegel, Ph.D.
Title: Heterogeneity of Triple Negative Breast Cancer Related To AIB1 Coactivator Expression and Drug Resistance
Breast cancer is the most diagnosed cancer and the most frequent cause of cancer mortality in women worldwide. Immunoreactive assays as well as gene expression profiling of breast cancer have shown a high degree of heterogeneity classifying it into subtypes associated to treatment response. The triple negative breast cancer (TNBC) subtype lacks the expression of hormone receptors (ER/PR) and the amplification of HER2 but it expresses basal keratin markers. TNBC represents 15-20% of all breast cancer cases in the United States (US). Attributable risk factors associated with TNBC include reproductive stage and age, race, and genetic factors. Mortality rates of TNBC are the highest in premenopausal women of African ancestry compared to women of European ancestry. The nuclear receptor coactivator Amplified in Breast Cancer 1 (AIB1) plays a major role in the progression of hormone and HER2-dependent breast cancers. Here, we examined AIB1’s role in TNBC. We determined that acute shRNA depletion of AIB1 significantly reduces cell survival in basal-like (BL) and mesenchymal (M) TNBC cell lines. Surviving cells with reduced AIB1 (AIB1 LOW ) can be maintained with stably low mRNA and protein levels of AIB1 in vitro and as xenografts in vivo. HCC1806-BL2 AIB1 LOW cells proliferate independent of serum supplementation and show reduced adherence to cell culture dishes. Also, AIB1 LOW cells from BL2- and M-TNBC subtypes show a significant reduced capacity to form tubes when cultured on a basement membrane. Similarly, chemotherapy treatment of BL2-TNBC cell line also resulted in a surviving AIB1 LOW population with impaired tube-formation capacity. Gene expression analysis of HCC1806-BL2 AIB1 LOW cell lines revealed a significant enrichment in pro-inflammatory pathways in vitro. Orthotopic injections using limiting dilutions of HCC1806-BL2 AIB1 LOW resulted in smaller size tumors and reduced incidence of pulmonary metastases in immunocompromised mice. NanoString gene expression analysis of xenograft tissues revealed that HCC1806-BL2 AIB1 LOW tumor cells from xenografts had significantly reduced gene expression related to tissue remodeling. Overall, our data suggest that subsets of TNBC cells with reduced AIB1 levels can result from therapeutic interventions. This subset may represent chemoresistant or reactivated dormant cells that under low densities might contribute to recurrence or metastasis of TNBC.
Friday, January 4 at 2:00pm to 4:00pm
Building D, Warwick-Evans Conference Room
4000 Reservoir Road, N.W., Washington
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