Dr Lucia Pirisi-Creek

Most of my research (conducted in close collaboration with Dr. Kim E. Creek) centers on cervical cancer, from the mechanisms that determine immortalization and progression to malignancy in HPV16-transformed human cells, to the epidemiology of HPV infection and cervical neoplasia in South Carolina women. A parallel project in the laboratory investigates the biology of ErbB2-positive breast cancer cells and their responses to Herceptin.
Role of the EGF receptor in HPV16-mediated human cell carcinogenesis: The transforming ability of oncogenic HPVs resides primarily in the oncoproteins E6 and E7. These proteins have a variety of activities and interact with many cellular proteins, however, the best described activities of E6 and E7 are also required for transformation in most cell systems: E6 degrades p53, and E7 binds and inactivates RB. Thus, the combined actions of these two oncoproteins promote genomic instability and transformation. We determined that the epidermal growth factor receptor (EGFR) plays a key role in the mechanisms by which HPV16 oncoproteins transform human epithelial cells. EGFR levels increase dramatically in human keratinocytes early after transfection with HPV16 DNA, and increase again (up to 10-fold) in growth factor independent HPV16-transformed cells. We determined that the early increase in EGFR levels is linked to the expression of the oncoprotein E6, which can induce EGFR mRNA in normal human keratinocytes. We also determined that normal human keratinocytes tolerate only relatively modest increases in EGFR signaling, and that E6 alone cannot overcome the mechanisms that prevent marked overexpression of the EGFR in these cells. E7 appears to abolish the senescence response to EGFR overexpression, and allow for cells overexpressing the EGFR to proliferate. We are investigating the molecular mechanisms by which E6 induces the EGFR and the contribution of E7 to this effect, using site-directed mutants of E6 and E7, and also RNA interference-based approaches.
Gene expression profiling of HPV-mediated transformation: We are using DNA microarrays to explore the gene expression profiles associated with HPV16-mediated transformation, with a particular emphasis on differential gene expression between low-passage cells – which are sensitive to TGF-beta and require exogenous growth factor to proliferate in culture – and differentiation-resistant cells –which are not growth inhibited by TGF-beta and are growth factor-independent. We aim at extending the same analysis to cervical specimens, in order to identify potential biomarkers of progression that may be useful to identify women at the highest risk for cancer, among the many who present with abnormal Pap smears.
Epidemiology of HPV infection and cervical cancer in South Carolina: Ann L. Coker (formerly at the Department of Epidemiology and Biostatistics of the University of South Carolina School of Public Health) and I have been following over time a population of low-income, primarily minority women for progression to high grade squamous intraepithelial lesions, in the attempt to learn more about the factors (in addition to persistent HPV infection, which we confirmed is a major determinant) that contribute to progression of HPV-mediated lesions to malignancy. These factors include life-style factors, smoking, contraceptive methods, and the adeno-associated virus. The latter appears to protect against progression in women infected with oncogenic HPV. More recently, in collaboration with Dr. Kathy Luchok, also of the USC School of Public Health we have investigated the role of stress in facilitating persistence of HPV infection. We are now initiating a new study of the determinants of HPV persistence in Caucasian and African-American female college students, aimed at identifying the immunological, HPV-associated, and life-style factors that contribute to persistent HPV infection, and how these may vary in different populations. Along the same lines, in collaboration with Subbi and Rajesh Mathur, at the Medical University of South Carolina, we are conducting a study of promising biomarkers of progression in tissue and serum samples from patients with cervical neoplasia.
Variant TGF-alpha precursors produced by alternative splicing differentially interact with ErbBs and modify Herceptin responses in ErbB2-positive breast cancer cells.
We discovered two variant forms of transforming growth factor-alpha precursor (proTGF-alpha), produced by alternative splicing of the proTGF-alpha mRNA. The variants are widely expressed in normal human keratinocytes as well as in cell lines derived from human tumors of epithelial origin, and some cancer cell lines that have lost expression of wild type (wt) proTGF-alpha still express the variant forms. These novel proTGF-alpha variants differ from wt proTGF-alpha only at the C-terminus, where two valine residues are replaced by other non- branched chain amino acids. The TVV motif at the C-terminus of wt proTGF-alpha is recognized by PDZ domain proteins and is believed to be necessary for correct trafficking and maturation of proTGF-alpha. Therefore, replacement of the valine residues with other amino acids is bound to profoundly affect interactions of proTGF-alpha with intracellular proteins. We went on to discover that the C-termini of wt and variant proTGF-alpha precursors mediate specific interactions with members of the ErbB family of receptors: while wt proTGF-alpha interacts with ErbB4, the two variants interact with ErbB2. These interactions lead to activation of ErbB2 in the absence of serum, in CHO cells expressing wt or variant proTGF-alpha. We recently determined that exogenous variant proTGF-alpha precursors decrease sensitivity of breast cancer cells to the growth inhibitory effects of Herceptin, a selective antibody directed against ErbB2 commonly used in the treatment of ErbB2-positive breast cancer.

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