Harikrishna Nakshatri

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https://hdl.handle.net/1805/17677

Enhancing Hormone Therapy and Chemotherapy Sensitivity of Breast Cancer

Breast cancers are broadly classified into estrogen receptor positive (ER+) and estrogen receptor negative (ER-) subtypes. Anti-estrogens (hormone therapy) and chemotherapy are treatment options for ER+ and ER- breast cancers, respectively. However, resistance to therapies is very common, and disease recurrence is associated with the spread of the diseases to multiple organs (metastasis). Dr. Nakshatri's research lab focuses on mechanisms of resistance to anti-estrogens and chemotherapy, predicting therapy resistance at the time of diagnosis, and developing effective combination therapies, particularly for metastasis.

His group has identified and commercialized biomarkers that may predict response to anti-estrogens, demonstrating that a protein complex min a subset of breast cancer plays a role in chemotherapy resistance and metastasis-research that, in collaboration with other institutions, is currently in phase I clinical trial. Additional work included circulating biomarkers that predict the effect of breast cancer on the general well-being of a patient and a new patent application on how to treat specific subtypes of breast cancer. His group also established a culturing method to grow and genomically characterize primary tumors and metastasis at the individual level.

Dr. Nakshatri's work to identify biomarkers of disease progression is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.

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Browsing Harikrishna Nakshatri by Author "Appaiah, Hitesh"

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    AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer
    (American Society for Microbiology, 2008-12) Bhat-Nakshatri, Poornima; Wang, Guohua; Appaiah, Hitesh; Luktuke, Nikhil; Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles; Badve, Sunil; Liu, Yunlong; Nakshatri, Harikrishna
    Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.