Uncovering Breast Cancer Predisposition Factors in Puerto Rico - Alvaro Monteiro, PhD (Moffitt) and Julie Dutil, PhD (PHSU)
Infiltrating Immune Cells in Breast Cancer Subtypes - Shari Pilon-Thomas, PhD (Moffitt) and Jaime Matta, PhD (PHSU)
Molecular Biology of Lung Cancer among Puerto Ricans - Doug Cress, PhD (Moffitt) and Pedro Santiago, PhD (PHSU)
In women, breast cancer is the most common invasive cancer worldwide with over 1 million new cases annually. Significant progress has been made in the identification of genetic factors that influence the risk of breast cancer. These include the two major predisposition genes BRCA1 and BRCA2, the tumor suppressor TP53, as well as many other genes. Intriguingly, most of these genes play important roles in the system that protects cells from damage to DNA. Damage to DNA can happen due to external environmental factors (e.g. radiation, cigarette smoking, and sun exposure). Individuals carrying defects in these genes are then less well equipped to fix breaks to their DNA and more prone to cancer.
Importantly, defects in the system that guards cells against damage to DNA and facilitate the development of tumors can be also exploited for treatment. For example, drugs that inhibit PARP1 (also participates in repairing damage to DNA) are highly effective for BRCA-linked tumors. Treatment with PARP inhibitors leads to the inactivation of an alternative way for DNA repair, leaving the tumor cells with a diminished ability to resist DNA damage induced by chemotherapy. Because the BRCA-mediated DNA repair is still intact in normal non-tumor cells, side effects are minimal. This strategy can be extended, provided that we know which genes that participate in DNA damage repair are defective in individual tumors.
Unfortunately, there is a dearth of information regarding which genes are preferentially inactivated in breast cancer in Puerto Rico (PR). Thus, our long term goal is to identify these genes and develop methods to accurately identify women at increased risk of developing breast cancer in PR. Our objectives are a) to identify the inherited changes that play a role in the DNA damage repair and are frequently inactivated in breast cancer in PR; and b) to identify the additional somatic (not inherited) changes prevalent in tumors arising in Puerto Rico that could inform therapeutic decisions.
The majority of studies on breast cancer subtyping and the prognostic value of immune infiltrates have included Caucasian women with little information generated in Hispanic breast cancer patients. The current project seeks to understand molecular differences among breast cancers of Hispanic and Caucasian women, specifically focusing on: 1) prevalence of intrinsic molecular subtypes and risk factors and 2) distribution and type of infiltrating immune cells by subtype. Our hypothesis is that Hispanic breast cancer patients will have distinct (1) incidences of breast cancer subtypes and (2) distributions of immune infiltrates in each one of these subtypes. This research project brings together our expertise in tumor micro-environments, breast cancer genomics and immune cell biology. We have access to currently banked samples as well future accrual of bio-specimens from the Puerto Rico Bio-bank and the Moffitt Cancer Center Tissue Core that provide a unique resource for studying breast cancer in Hispanic patients. Our long-term goals are to develop bio-markers for breast cancer disease progression and to determine which Hispanic breast cancer patients would benefit from personalized immunotherapy.
While lung cancer is a leading killer among all ethnic groups, emerging data suggest that the genetic mutations that drive lung cancer differ in frequency and nature among different ethnic groups. As one example, recent work demonstrates that when compared to Whites, Latino and Asian populations have a much higher rate of mutations in the gene coding for the Epidermal Growth Factor Receptor involved in the response to proliferation-inducing signals. At this point it is not clear why different ethnic groups differ in the genetic mutations that drive their lung cancers. However, understanding these mutations is of paramount importance as their nature determines treatment choices and could predict therapeutic outcomes. This is particularly important as novel anti-cancer drugs emerge that specifically target the protein products of these mutant genes. Therefore it will become increasingly important to understand the specific nature of mutations that drive lung cancer among various ethnic groups in order to make treatment as ethnic-specific, and therefore as effective, as possible. Currently, there are no significant databases addressing the mutations that drive lung cancer among Puerto Ricans, even though lung cancer is the leading cancer killer among Puerto Rican men and second killer among Puerto Rican women. This project will fill this knowledge gap by utilizing tumor tissue samples from Puerto Rican lung cancer patient to characterize and catalog mutations and epigenetic changes in candidate genes known to play an important role in lung cancer formation such as TP53, EGFR, CDKN2A and KRAS. This will produce valuable data on the genetics and the molecular biology of lung cancer in Puerto Ricans, which will in turn affect genetic testing and treatment recommendations for Puerto Ricans patients if the alterations characterized in this project can be clinically targeted and their molecular consequences characterized.