As a born and raised Kansan, and recently winged Jayhawk, I feel fortunate to be part of the MD/PhD program at the KU School of Medicine!
I graduated from the University of Kansas with a B.S. in Cell Biology in 2006. While at KU, I had the privilege of studying the adenomatous polyposis coli (APC) tumor suppressor protein and its role in colorectal carcinogenesis in Dr. Kristi Neufeld’s laboratory in the Department of Molecular Biosciences. It was this experience that ignited my passion for cancer biology and fueled my interest in pursuing the dual degree.
My primary research interests remain in tumor biology. I am now in the laboratory of Dr. Roy Jensen in the Department of Pathology and the KU Cancer Center. Our laboratory aims to understand the functions of the BRCA1 tumor suppresor gene, mutations in which have been identified as the causative genetic lesion in a large proportion of hereditary breast and ovarian cancers. While the significance of BRCA1 function in hereditary malignancies has been established, its role in sporadic breast and ovarian carcinogenesis is poorly characterized. I currently have two major interests:
The first is concerning the role of BRCA1 in chemo- and radiotherapy resistance in sporadic breast cancer. Approximately 30-40% of sporadic human breast cancers demonstrate decreased expression of BRCA1, though the BRCA1 gene remains intact. Previous studies have attributed this phenomenon to BRCA1 promoter methylation and ubiquitination of BRCA1 protein. Though BRCA1 function is lost early in the progression of sporadic cancers, tumors which have become refractory to chemo- and radiotherapy through continued treatment commonly demonstrate increased BRCA1 expression. Since BRCA1 is an integral component of the homology-directed DNA repair machinery, its overexpression likely confers resistance to genotoxic anti-neoplastic agents. I am currently investigating the interaction between the molecular chaperone pathway and BRCA1 in order to evaluate the potential use of heat shock protein inhibitors as chemo- and radiotherapy potentiation agents.
The second interest, which will be the topic of my dissertation, will concern the role of BRCA1 in the epithelial-mesenchymal transition (EMT) and breast cancer stem cell fate. It is well-established that tumors which arise in women with inherited BRCA1 mutations are almost exclusively basal-like breast cancers (BLBCs). Additionally, sporadic BLBCs demonstrate decreased expression of BRCA1 when compared to sporadic luminal tumors. These findings, in conjunction with recent in vitro and in vivo studies, demonstrate that loss of BRCA1 through either mutational inactivation or altered expression leads to an absolute defect in the differentiation of basal/myoepithelial cells into differentiated luminal cells and profound expansion of the stem/progenitor cell population. Furthermore, BRCA1-deficienct BLBCs almost universally display a degree of squamous and/or mesenchymal differentiation, suggesting that BRCA1 may antagonize induction of the epithelial-mesenchymal transition. This idea is supported by the finding that TGFβ, a major positive regulator of EMT, negatively regulates BRCA1. Recent studies have linked the EMT process with stem/progenitor cell function in that the EMT promotes the generation and self-renewal capacity of stem/progenitor-like tumor initiating cells in vitro. Since BRCA1 has a critical role in the repair of DNA by the high-fidelity homologous recombination pathway, the absence or downregulation of BRCA1 in hereditary and sporadic malignancies may contribute to induction of the EMT and accumulation of genetically unstable stem/progenitor cells which are destined to produce aggressive basal-like breast cancers. Given these findings, it is plausible to assert that increasing BRCA1 expression pharmacologically may present a novel chemopreventative stategy by simultaneously overcoming the differentiation defect observed in BRCA1-deficienct sporadic malignancies and inhibiting protumorigenic EMT-like programs.
Ultimately, I hope to become a radiation oncologist at an academic medical center where I can combine my training in medicine and molecular biology to study the underlying causes of human cancers and translate this knowledge into novel therapies.
Should you have any questions about me or about the M.D./Ph.D. program in general, please feel free to e-mail me at sstecklein@kumc.edu.
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