Research Activities

My main research expertise is in the area of toxicology. Since my recruitment at PSM, I have worked in three areas within that large interdisciplinary field of toxicology. During the last seven years, I have been primarily focused in the field of clinical cancer research studying the role of DNA repair as a risk factor for skin and breast cancer.

The overall goals of my laboratory are to: a) define the role of DNA repair in skin and breast cancer susceptibility and resistance to chemotherapeutic agents b) to identify DNA repair genes that are associated with significant changes in risk to skin and breast cancer, c) study mechanisms involved in the regulation of DNA repair gene expression by activated Stat3 signalling in melanoma skin cancer, d) determine how genetic and environmental factors influence the risk of skin and breast cancer at the populational level.

Currently, I am particularly interested in the following questions:

1. What is the role of DNA repair in the development of skin and breast cancer?
2. What are the key DNA repair genes associated with a significant increase or reduction in skin and breast cancer?
3. What are the mechanisms involved in the regulation of DNA repair gene expression by activated Stat3 signalling in melanoma skin cancer?
4. Are there genes that can be utilized to produce a “molecular signature” that can predict metastasis in melanoma?

During the last six years, we have conducted in Puerto Rico a large case-control study in the molecular epidemiology of non-melanoma skin cancer under the sponsorship of NASA and NIH (RCMI Program grant 2G12-RR03050-19). This study was concluded on June 30, 2006. It represented the largest and most extensive study in the world with approximately 475 cases of NMSC recruited and 360 controls. In addition, we have recruited in the last three years approximately 70 participants with melanoma. As a result of this effort, several ancillary studies have been developed and summarized here.

The focus of this study has been to examine the hypothesis that reduced DNA repair capacity (DRC) increases the risk to melanoma and non-melanoma skin cancers (NMSC) in PR. A host cell reactivation assay developed by my mentor, Dr. L. Grossman, Johns Hopkins University (recently deceased) is utilized with a reporter gene to measure global DRC in blood lymphocytes. Data from clinical case-controlled retrospective studies is stratified by DNA repair level and adjusted for age, skin type, familial history of skin cancer and severe sunburns in a lifetime in order to calculate odds ratios and skin cancer risk factors. We have shown (Matta et al. 2003) that persons with NMSC have a statistically significant reduction of 32% in the age-adjusted DNA repair capacity (DRC). Utilizing logistic regression analysis, we have also shown that for every 1% reduction in DRC (in relation to controls without NMSC which have an average DRC of 9% in their lymphocytes), the risk of NMSC increases 21% and the risk developing melanoma increases 11%.

The clinical implications of this approach are expected to have a significant impact on the early detection and prevention of melanoma and NMSC in Puerto Rican populations. The knowledge obtained from this study is significantly contributing to the development of effective strategies of skin cancer prevention and control using the Puerto Rican population, which is exposed to high UV levels throughout the year, as a model (Ramos et al. 2004) . In collaboration with Dr. Richard Jove and Dr. Adam Riker at Moffitt Cancer Center in Tampa, we are undertaking a study to examine by means of gene microarrays the differential expression of DNA repair and other genes that are involved directly or indirectly with tumorigenesis in melanoma. We are also using microarray technology to identify specific genes associated with the genetic progression of melanoma both in Florida and in Puerto Rico. Finally, polymorphisms in codon 751 of the XPD gene are being studied by Dr. Edu Suarez ( University of Puerto Rico, Ponce) to explain the early onset of basal cell carcinoma in PR.

My main clinical research interest, in collaboration with Dr. Adam Riker, Dr. Richard Jove and Dr. Ralf Buettner, is to identify genes associated with the malignant progression of melanoma in tumor samples from Florida and Puerto Rico (PR). Two abstracts of this work will be presented by Dr. Riker at the Third annual international Melanoma Research Congress to be held  in The Netherlands on September 13 -16, 2006.

Focus area 1: DNA repair and gene expression associated with susceptibility to breast carcinoma. Funding source: MBRS/SCORE grant #: S06 GM 08239-20 (2006-2009, funding pending).

his study represents the first large-scale population effort utilizing a comprehensive and innovative approach aimed at correlating how DRC, changes in expression of DNA repair genes and key pathological and epidemiological characteristics of BC influence the risk of this disease. The novel genetic and phenotypic traits associated with BC that will be identified in this study, will provide a means to more accurately estimate the overall risk of BC. By studying the expression of DNA repair genes, we may better understand the pathogenesis of breast carcinoma and to identify women at high risk by using combined genetic and environmental risk factors (breast cancer prevention). Identification of specific DNA repair genes associated with BC risk may serve in predicting the prognosis and therapeutic outcome of breast carcinoma patients. This may provide a rationale for developing future patient-based optimal selection of chemotherapeutic agents and radiotherapy protocols. In order to accomplish these general objectives, studies with the following specific aims are proposed:

Back to top

Specific Aims

1. Compar e the DNA repair capacity (DRC) in women with and without breast carcinoma in Puerto Rico using a host cell reactivation assay that provides a direct measurement. It is hypothesized that participants with breast carcinoma have a lower age-adjusted DRC than women without breast carcinoma.

 2. Obtain epidemiological data from participants in order to determine risk factors for breast carcinoma. Each participant (controls and cases) will be administered an epidemiological questionnaire soliciting information on variables that can provide an estimate of breast carcinoma risk in relation to familial, genetic, hormonal and environmental factors. Statistical correlations between the various study variables and risk of developing breast carcinoma will provide valuable information for the development of effective strategies for cancer prevention and control for future studies.

3. Compare whether the levels of expression of DNA repair genes is correlated with the DNA repair capacity of women with breast carcinoma. It is hypothesized that women with BC have an altered expression of key DNA repair genes. T he expression of DNA repair genes in BC tumors will be analyzed in women with low, normal, and high DRC. Microarray analysis will be utilized to identify potential DNA repair genes associated with the risk of breast carcinoma and to test whether candidate DNA repair genes can be utilized to predict DNA repair capacity of women with breast carcinoma.

4. Examine whether tumor grade and size and presence of axillary lymph node metastasis are associated with the level of DNA repair capacity and levels of expression of DNA repair genes. The pathology report will be analyzed for the presence of axillary lymph node metastasis, the size of the tumor, the histological grade, and type and sub-type of breast carcinoma. It is hypothesized that BC cases with a lower DRC have a higher tumor grade, larger size, and positive axillary lymph node metastasis when compared with BC cases with higher DRC. It is also hypothesized that BC cases with a significant alteration in the expression of DNA repair genes have a higher tumor grade, larger size, and positive axillary lymph node metastasis than BC cases with a normal expression of DNA repair genes.

Focus area 2: Cutaneous human papillomavirus infection and non-melanoma skin cancer in the U.S. and Puerto Rico . Funding Source: Cooperative Planning Grant for Comprehensive Minority Institution/Cancer Center Partnership (U-56) between H. Lee Moffitt Cancer Center and Ponce School of Medicine (funding pending). This is a joint effort with Dr. Dana Rollison (HLMCC). The objectives of this 2-year pilot study are to demonstrate the feasibility of data collection and to obtain estimates of HPV antibody prevalence in NMSC cases and controls from both populations to be used in sample size calculations for future grant applications. Additionally, potential interactions between HPV infection and known skin cancer risk factors, such as tanning ability and DNA repair capacity will be explored. Information collected in the larger study will be used to investigate the association between HPV infection and NMSC in two ethnically diverse, chronically sun-exposed populations. The ultimate goal of this research is to further our understanding of the relationship between HPV and NMSC, so that additional prevention strategies for NMSC may be developed.

Specific Aims:

1. Obtain blood specimens and questionnaire data from 100 NMSC cases from the University of South Florida dermatology clinic in Tampa, FL and 100 cases from Puerto Rico in one year, which will include prospectively recruiting 100 NMSC cases in Tampa and recontacting 56 NMSC cases who have already being recruited for a skin cancer study in Puerto Rico.
2. Using both prospectively obtained and archived samples, measure levels of antibodies to the L1 proteins of 14 Genus Beta HPV types (5, 8, 9, 15, 17, 20, 23, 36, 38, 49, 75, 76, 92, 93) and determine the seroprevalence of these antibodies in a total of 200 NMSC cases and 200 controls.
3. Estimate the association between HPV antibodies and NMSC.

Focus area 3: Molecular identification of bacterial and fungal species in Sahara dust samples (Pilot Project in collaboration with Roy A. Armstrong, Ph.D, University of Puerto Rico, Mayaguez, Puerto Rico). This project is being directed by Dr. Edu Suarez, Postdoctoral Researcher PSM and Assistant Professor, UPR, Ponce.

Dust clouds which move from the Sahara desert across the Atlantic Ocean, impact the Caribbean, Central America and the South East of US between the months of June and October and the North eastern Amazon basin from February to April. The estimates of the quantity of this dust transported into de atmosphere have been calculated to rage between 500 millions to 1 billion annually. Although the Saharan dust serve as a nutrient transporter to several ecosystem’s members, it also acts as a spreader of a wide variety of organisms (fungi, viruses, bacteria) and their biologically derived products (spores, mycotoxins, endotoxins) that can be pathogenic to plants, marine environments and humans. Current research efforts to identify the organisms which are brought by the Saharan dust across the Atlantic and that might be causing the detrimental results in these regions include the culturing of viable specimens, the PCR and the DNA sequencing testing. Several fungal and bacterial species, as well as viruses which can be threatening to the human health, have been isolated in cultures and their identity confirmed by PCR and DNA sequencing techniques (Griffin 2001). However, it has been postulated that the assessment of the species by employing these methods contributes with less than 1% of the total burden comprising the tested samples. To overcome the limitations of current identification methods mentioned above, we are utilizing the PCR and the DNA sequencing, not only as a validation tool for the species identity but primarily, as a direct identifier of the existent organisms collected in an oceanographic cruise off the coast of Africa.

Back to top

Extramural Funding

Current Support

Title: “ Characterization of microorganisms and human health effects associated with Sahara dust ”.Source: NASA, Budget: $16,878 (awarded to Dr. R. Armstrong). (Pilot Project in collaboration with Roy A. Armstrong, Ph.D, University of Puerto Rico, Mayaguez, Puerto Rico, Hector D’Antoni, Ph.D., NASA Ames Research Center, Ames, California

Title: “ DNA repair capacity and gene expression associated with susceptibility to breast carcinoma”. Source: National Institutes of Health (NIH), MBRS/SCORE Program, Budget: $ 602,436 (direct cost only) 2006-2009.

Title: “ Cutaneous human papillomavirus infection and non-melanoma skin cancer in the U.S. and Puerto Rico” Funding Source: Cooperative Planning Grant for Comprehensive Minority Institution/Cancer Center Partnership (U-56) between H. Lee Moffitt Cancer Center and Ponce School of Medicine. Budget: $100,000 (direct costs only) 2006-2008.

Back to top