- BS, Bioinformatics, University of Colombo
- MS, Entomology, Oklahoma State University
Enter program in 2012
Minority women, specifically African Americans (AAs), are significantly more likely than Caucasians to develop early onset breast cancer (EOBC) that carries with it a substantially aggressive and worse prognosis. The mechanistic basis for this persistent health disparity is largely unexplored, but it is highly likely that genetic susceptibilities contribute, both independently and in collaboration with other risk factors. Human genetic analyses have identified proline-coding variant of p53 codon 72 polymorphism that is more common in African descendants than the European counterparts. Numerous epidemiological studies have implicated this SNP in susceptibility to various cancers including female breast cancer (BrCa). In vitro studies have shown that the two variants differ in the ability to induce apoptosis. The epidemiological studies have shown that early pregnancy does not provide a similar protection against BrCa in AA and white women, and we believe that this lack of protection also contributes to early onset, more aggressive disease. Studies demonstrate that the hormonal milieu of pregnancy induces p53 in the mammary gland contributing to pregnancy-induced protection. Based on these studies, we hypothesize that racially disproportionate p53 polymorphisms are critical contributors to the increased incidence of and poor outcomes associated with EOBC in women of African ancestry.
To investigate the above, I use a humanized mouse model, in which the exon 4, where the variants are located, of the human p53 was “knocked-in”. Animals of p53mWT/mWT, p53P/P and p53R/R genotypes will be exposed to the hormonal milieu of a full-term pregnancy to observe the differences in temporal p53 expression. To provide insight into the ability of pregnancy to induce protection against environmentally relevant DNA damage, I will expose control (vehicle-treated) and E+P-treated animals of three genotypes to X-ray. We will also assess the ability of pregnancy to inhibit DMBA-induced mammary carcinogenesis in animals of the three genotypes and the MMTV-Erbb2 mammary cancer model will be used to observe the effects of p53 polymorphisms on early and aggressive mammary tumor development. Further, we will evaluate the role of p53 codon 72 genotype in pathologically confirmed breast cancer cases to allow the findings to be translated to a human population.
Broader Impacts of Research Project:
The significance of this project lies in the overall goal of investigating biological and genetic mechanisms underlying the increased incidence of early onset, highly aggressive and treatment refractory breast cancer (BrCa). It is the increased tendency of minority women to develop early onset, aggressive disease that we hypothesize is an important contributor to BrCa health disparities. We will use relevant and highly manipulable in vivo models to test this novel hypothesis, which is firmly grounded in results from epidemiology, genetic and molecular studies. The use of relevant animal models allows recapitulation and intricate manipulation of the multifactorial contributors to EOBC in an authentic in vivo milieu.
The proposed experiments will yield substantial new knowledge about the causes of early onset breast cancer (EOBC) and provide insights into the previously underappreciated impact of racially disparate p53 polymorphisms on BrCa development. An improved understanding of the causes and risks of EOBC carries with it the promise of effective and achievable prevention strategies, such as modulation of dietary, environmental or other factors.
- Zhang X., He Y, Cao, X, Gunaratna R.T., Chen Y., Blissard G., Kanost M., Jiang H. (2015) Phylogenetic analysis and expression profiling of the pattern recognition receptors: insights into molecular recognition of invading pathogens in Manduca sexta. Insect Biochem Mol Biol. pii: S0965-1748(15)00024-7. (http://www.ncbi.nlm.nih.gov/pubmed/25701384).
- Gunaratna R.T., Jiang H. (2013) A comprehensive analysis of the Manduca sexta immunotranscriptome. Developmental and Comparative Immunology, 39(4) , pp. 388-398 (http://www.ncbi.nlm.nih.gov/pubmed/23178408).
- Zhang S., Gunaratna R.T., Zhang X., Najar F., Wang Y., Roe B., Jiang H. (2011) Pyrosequencing-based expression profiling and identification of differentially regulated genes from Manduca sexta, a lepidopteran model insect. Insect Biochem Mol Biol 41 (9) : 733-46 (http://www.ncbi.nlm.nih.gov/pubmed/21641996).
Memberships and Activities:
- President (2014/15), GSC Representative (2013/14) – Genetics Graduate Students’ Association, Member (since 2012)
- President – Sri Lankan Students’ Association (2013/14) , Member (since 2012)
- Memeber - Texas A&M University Cricket team (since 2013)
- Member - Sri Lankan Cricket Club, Houston tape-ball Cricket League (since 2014)