Maria Ramos, PhD, Research Assistant Professor of Pathology
ERK5-dependent Chemoresistance in Mesothelioma
Malignant 
Mesothelioma (MM), an aggressive malignancy recently associated with environmental exposure to asbestos is a fatal
tumor resistant to therapy. The incidence of mesothelioma is rising, creating a pressing need for new therapeutic strategies.
Although the development of asbestos-related diseases is complex, a number of studies suggest that reactive oxygen species (ROS)
mediate asbestos-induced pathogenesis. In an environment of increased oxidative stress as the one found in the pleura, mesothelial
cells might develop particular defenses against the oxidative environment leading to the development of mesothelioma. This
particular conditioning environment could be one of the causes of the resistance of mesothelioma to ROS producing anticancer
drugs. During our efforts to elucidate the molecular events that lead to the high chemoresistance of this tumor to ROS producing
anticancer drugs, particularly Carmustine and Doxorubicin, we have found a sustained overexpression and activation of the redox
sensitive kinase Extracellular Signal-Regulated Kinase 5 (ERK5) in mesotheliomas, when compared to normal mesothelial cells, and
the use of dominant negative constructs against ERK5 have resulted in an increased sensitivity to these alkylating and oxidant
producing anticancer drugs in vitro. In this study we will test using a mouse orthotopic model, the hypothesis that expression of
ERK5, results in an increased drug resistance to Carmustine in vivo.
Mercedes Rincón, PhD, Associate Professor of Medicine
Role of MCJ in Breast Cancer Chemoresistance
Chemotherapy 
has been and still is one of the most effective and widely used means of treating breast
cancer. Anthracyclines (doxorubicin) and taxanes (paclitaxel) are the most commonly used drugs due to their relatively high
effectiveness during the initial response. However, the resistance or sensitivity to anthracyclines/taxanes during initial and
later treatment varies among individuals and there are no markers that distinguish responders from non-responders. Determining
which group of markers can identify cancer patients who will benefit from this therapy and those who will not is a significant challenge.
Our group has been working on the identification of some of these markers. We have shown that
autocrine production of IL-6 by breast cancer cells promotes multidrug resistance. Recently we have focused our interest on MCJ,
a newly identified member of the DnaJ protein family of co-chaperones, and its role on breast cancer drug resistance. A recently
published study about MCJ has shown an inverse correlation between the expression of MCJ and multidrug restistance in ovarian
cancer cells and primary ovarian tumors. Our preliminary data show that MCJ is also expressed in drug-sensitive breast cancer
cells, but not in multidrug resistant breast cancer cells. Inhibition of MCJ expression by RNAi in drug-sensitive cells increases
their resistance to doxorubicin. Interestingly, we also found that IL-6 inhibits MCJ expression in breast cancer cells. We
propose that the loss of MCJ expression increases the resistance of breast cancer cells to chemotherapy both in vivo and
in vitro. We also propose that IL-6 induces multidrug resistance by inhibiting MCJ gene expression through methylation in
breast cancer cells.
Viswanathan Muthusamy, PhD, Bosenberg Laboratory
The Role of DNA Methylation in Malignant Melanoma
Malignant 
melanoma is the most lethal form of skin cancer. Early metastases are characteristic of melanoma
and indicative of a poor prognosis as current therapeutic modalities have little effect on survival. The lack of accurate prognostic
indicators and effective therapies emphasizes the need for a better understanding of genetic, epigenetic, and phenotypic changes in
melanoma formation and progression. Genetic alterations that occur frequently in melanoma include loss of the CDKN2A locus
which encodes two tumor suppressor genes — p16INK4A and p14ARF, and activation of the
MAP kinase pathway by mutations either in BRAF or RAS. Recent studies have shown that DNA hypermethylation is a
common mechanism of silencing expression of tumor suppressor genes. Near-complete suppression of polyp formation was observed in the
ApcMin mouse model of colonic neoplasia by hypomorphic Dnmt1 alleles. However, loss or decrease in Dnmt1 activity has
also resulted in increase formation of lymphomas in another mouse model. We propose to study the effect of melanocyte-specific
inactivation of Dnmt1 on melanocyte survival and growth and to examine the effects of Dnmt1 inactivation on melanoma formation in
a mouse model of melanoma.