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Harikrishna Nakshatri, BVSc., PhD
Professor of Surgery
Marian J. Morrison Chair in Breast Cancer Research
Associate Director of Education
Co-Program Leader, Breast Cancer Program
Goal: To understand the unique characteristics of breast cells that give rise to breast cancer in women with inherited mutations in the BCRC genes.
Impact: Women who carry a mutated BRCA gene have a high risk of breast cancer. BRCA-driven breast cancers are more likely to occur at a young age and can be very aggressive. However, not all BRCA mutations carriers will develop breast cancer. Dr. Nakshatri is studying the differences in breast cells in BRCA mutation carriers and non-carriers to identify biomarkers that may help predict the risk of breast cancer, but may also inform early detection, as well as non-invasive prevention strategies.
What’s next: Dr. Nakshatri and his team will study the molecular and cellular composition of breast tissue in BRCA1/2 mutations carriers to identify the genetic changes that are not present in the breast cells of non-BRCA mutation carriers. In this way, they hope to identify a genetic profile that can be used for risk prediction and early detection. The normal breast contains multiple types of cells from which breast cancer can originate and may differ between individuals. In this study, Dr. Nakshatri hopes to identify the cell types in BRCA mutations carriers that are particularly vulnerable to cancer development. Understanding what is different in the breast cells of BRCA mutation carriers who do versus those who do not develop breast cancer has enormous potential in personalized risk prediction, early detection and treatment of what can be a very aggressive type of breast cancer.
Full Research Summary
Research area: Identification of early markers of breast cancer in women with a strong hereditary predisposition for the disease to improve risk prediction and early detection.
Impact: Cells that harbor defective BRCA genes are especially vulnerable to the cancer-causing effects of DNA damage. In the case of an inherited BRCA mutation, every cell in the body carries the same mutation but not the same risk of cancer. In this study, Dr. Nakshatri hopes to characterize the cells in the breast of BRCA mutation carriers that give rise to cancer. This work will not only help to explain why not all BRCA mutations carriers develop cancer, but also to reveal BRCA-ness markers that could identify non BRCA mutation carriers with a high risk of breast cancer.
Current investigation: Previous work by Dr. Nakshatri has shown that in the normal breast, both the composition of breast tissue and the genetic profile of breast cells vary greatly. This variability helps to explain the uniqueness of every breast cancer. In the current study, he and his colleagues will employ single cell analysis of breast cells from BRCA mutation carriers and non-carriers to determine what cell types may make BRCA mutation carriers particularly susceptible to breast cancer.
Harikrishna Nakshatri, BVSc, PhD, is the Marian J. Morrison Chair of Breast Cancer Research and professor of surgery, biochemistry and molecular biology at the Indiana University School of Medicine. He is also the Associate Director for Education at the Indiana University Simon Comprehensive Cancer Center.
Dr. Nakshatri studies the molecular drivers of therapy resistance in breast cancer. His laboratory was the first to identify the role of the protein complex, NF-kappaB, which controls genes that respond to environmental stress and infection in triple-negative breast cancer. He also identified biomarkers that may predict response to anti-estrogen therapy. Utilizing normal breast tissues of women of different ethnic background, his group has discovered genetic ancestry-dependent heterogeneity in the normal breast, which has important implications on how tumors are characterized for genomic abnormalities. His recently published studies may enable us to understand why hormone-responsive breast tumors are more common in women of European ancestry and why triple-negative breast cancers are aggressive in women of African ancestry. Additionally, his group is mapping the normal breasts as well as the breasts of BRCA1/2 mutation careers at single cell resolution using single cell sequencing techniques. These efforts may lead to classification of breast cancer based on “cell-of-origin” of tumor. He is using systems biology approaches to understand organ-specific breast cancer metastasis and developing patient-derived tumor models that reflect organ-specific metastasis and therapy resistance.