Harikrishna Nakshatri, PhD
Marian J. Morrison Professor of Breast Cancer Research
Dr. Nakshatri’s laboratory research interests are on heterogeneity in normal breast, the mechanisms of anti-estrogen resistance and metastasis in breast cancer. Ongoing research in his lab includes elucidating the mechanisms by which the serine/threonine kinase AKT alters estrogen signaling and confers anti-estrogen resistance in breast Cancer. One of the projects focuses on how loss of Dependence Receptor UNC5A leads to anti-estrogen resistance and metastasis of estrogen receptor positive breast cancer. His laboratory has identified and commercialized biomarkers that may predict response to anti-estrogen therapy. His laboratory was the first to demonstrate constitutive activation of NF-kappaB in a subset of breast cancer. Activated NF-kappaB confers chemotherapy resistance and enhances metastasis. An inhibitor of NF-kappaB developed by his lab in collaboration with other institutions is currently in phase I clinical trial for cancer. His laboratory is also investigating the mechanisms of organ-specific metastasis and the role of cancer stem cells in chemoresistance and metastasis. Using the normal breast tissue from Susan G. Komen for the Cure Tissue Bank, his group has shown ethnicity-dependent and ethnicity-independent heterogeneity in the normal breast. His group has also established a culturing method to grow tumors, and tumor adjacent-normal, and metastasis to genomically characterize tumors/metastasis at single cell level. NIH, Department of Defense, American Cancer Society, Susan G. Komen for Cure, Department of Veterans Affairs and other private foundations funded his research. He is the author or co-author of >130 publications with >14,000 citations. He has served/serving in scientific review committees of NIH, Department of Defense, Italian Association for Cancer Research, and Susan G. Komen for Cure. He is currently a member of the NIH Cancer Molecular Pathobiology Study Section. He is also in the editorial boards of scientific journals and an Associate Editor of Cancer Research, a premier journal from American Association for Cancer Research and Associate Editor-in-Chief of Cancer Management and Research. He has trained over 20 post-doctoral fellows, surgical residents, and medical students. In his role as the Associate Director of Education at the Indiana University Simon Cancer Center (IUSCC), he is responsible for developing educational activities of the cancer center and a training program in cancer biology.
Nakshatri H, Appaiah HN, Anjanappa M, Gilley D, Tanaka D, Badve S, Crooks P, Mathews W, Sweeney C, and Bhat-Nakshatri, P. (2015). NF-?B dependent and independent epigenetic modulation using the novel anti-cancer agent DMAPT. Cell Death and Disease 6:e1608.
Riesa M Burnett, Kelly Craven, Purna Krishnamurthy, Chirayu P Goswami, Sunil Badve, Peter Crooks, William P Mathews, Poornima Bhat-Nakshatri and Harikrishna Nakshatri (2015). Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells. Oncotarget 6:12682-96.
Perkins S, Bales C, Vladislav T, Althouse S, Miller KD, Sandusky G, Badve S, and Nakshatri H. (2015). TFAP2C expression in breast cancer- correlation with overall survival beyond 10 years of initial diagnosis. Breast Cancer Research and Treatment 152:519-31.
Jin K, Park S, Teo WW, Korangath P, Cho SS, Yoshida T, Gyorffy B, Goswami CP, Nakshatri H, Cruz LA, Zhou W, Ji H, Su Y, Ekram M, Wu Z, Zhu T, Polyak K, and Sukumar S. (2015). HOXB7 is and ERa cofactor in the activation of HER2 and multiple ER target genes leading to endocrine resistance. Cancer Discovery 5:944-59#
Nakshatri H, Anjanappa M, and Bhat-Nakshatri P. (2015). Ethnicity-dependent and ethnicity-independent heterogeneity in healthy normal breast hierarchy impacts tumor characterization. Nature Scientific Reports 5:13526.
Bhat-Nakshatri P, Goswami CP, Badve S, Magnani L, Lupien M, and Nakshatri H. (2016). Molecular insights of pathways resulting from two common PI3KCA mutations in breast cancer. Cancer Research 76:3989-4001.
Anjanappa M, Burnett R, Zieger MA, Merfeld-Clauss S, Wooden W, March K, Tholpady S, and Nakshatri H. (2016). Distinct effects of adipose-derived stem cells and adipocytes on normal and cancer cell hierarchy. Molecular Cancer Research 14:660-671.
Anjanappa M, Angelo Cardoso, Lijun Cheng, Safa Mohamad, Andrea Gunawan, Susan Rice, Yan Dong, Lang Li, George E. Sandusky, Edward F. Srour and Harikrishna Nakshatri (2017). Individualized breast cancer characterization through single cell analysis of tumor adjacent-normal cells. Cancer Research 77:2759-2769.
Anjanappa M, Hao Y, Simpson ER, Bhat-Nakshatri P, Nelson JB, Tersey SA, Mirmira RG, Cohen-Gadol A, Saadatzadeh MR, Li L, Fang F, Nephew KP, Miller KD, Liu Y and Nakshatri. H. (2018). A system for detecting high impact-low frequency mutations in primary tumors and metastasis. Oncogene 37:185-196.
Wang R, Bhat-Nakshatri P, Padua MB, Prasad MS, Anjanappa M, Jacobson M, Finnearty C, Sefcsik V, McElyea K, Redmond R, Sandusky G, Penthala N, Crooks PA, Liu J, Zimmers T, and Nakshatri H. (2017). Pharmacological dual inhibition of tumor and tumor-induced functional limitations in transgenic model of breast cancer. Molecular Cancer Therapeutics 16:2747-2758.
Beg F, Wang R, Saeed Z, Devaraj S, Masoor K and Nakshatri H (2017). Inflammation-associated microRNA changes in circulating exosomes of heart failure patients. BMC Research Notes 10:751.
Padua MB, Bhat-Nakshatri P, Anjanappa M, Prasad MS, Hao Y, Liu S, Wan J, Liu Y, McElyea K, Jacobsen M, Sandusky G, Althouse S, Perkins S and Nakshatri H. (2018). Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis. Breast Cancer Research 20:35.
R3 C218C SGEN
Titles & Appointments
- Professor of Surgery
- Professor of Biochemistry & Molecular Biology
Currently, his group is engaged in six main research projects.
1) Mechanisms associated with systemic effects of cancer. Nakshatri’s group has observed that cancer-derived factors alter the expression and release of microRNA miR-486 from heart and skeletal muscle. Current studies are to determine whether loss of miR-486 leads to systemic effects of cancer including functional limitation and cachexia. Animal models are being used to test miR-486 as therapy to overcome cancer-associated systemic effects.
2) Heterogeneity in normal and cancer with a focus on cancer stem cell hypothesis. His lab has established procedures to grow normal breast cells from core needle biopsies of healthy donors to study inter-individual heterogeneity and ethnicity-dependent differences in normal breast biology. Ethnicity-dependent differences in the methylome of normal breast has recently been established and mechanistic studies are planned
3) Therapeutic targeting of breast cancer stem cells. His group has used connectivity map and various bioinformatics tools to identify FDA approved drugs that target breast cancer stem cells. All trans retinoic acid identified in this screen is now being evaluated.
4) Organ-specific metastasis. His group is culturing liver and brain metastasis of various cancers and subjecting these cells to whole genome analysis. This study is aimed to test that hypothesis that primary tumors and metastases evolve in parallel and metastases acquire independent mutations that enable cancer cells to adapt to the organs of metastasis. The long-term goal is to use these genomic information to develop metastasis-targeted therapy.
5) The role of AKT1 isoform in estrogen addiction phenotype of breast cancer. His group has found PI3K mutation leads to preferential activation of AKT1 but not AKT2 isoform. AKT1 is essential for estrogen-induced gene expression, proliferation and response to clinically used PI3K inhibitors.
6) Estrogen Receptor signaling in normal breast epithelial cells. This project will determine how estrogen receptor differs in its activity in normal and tumor cells. His group for the first time has developed immortalized breast epithelial cells naturally expressing estrogen receptor. The goal is determine genome wide estrogen receptor binding pattern in immortalized and transformed breast epithelial cells.
American Association of Cancer Research (AACR)
Desc: Outstanding Achievement Award
Org: Walther Cancer Institute
Desc: Inaugural Michael K Gust award for Innovative Research
Desc: Prestigious External Recognition Award