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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Now showing 1 - 10 of 98

Indiana Center for Breast Cancer Research
(Office of the Vice Chancellor for Research, 2014-04-11) Nakshatri, Harikrishna; Gilley, David P.; Wells, Clark D.; Nephew, Kenneth; Radovich, Milan; Guise, Theresa; Bales, Casey; Perkins, Susan; Badve, Sunil; Vladislav, Ioan Tudor; Miller, Kathy
The mission of IUPUI breast cancer signature center is to address prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts improve resources for breast cancer research and efforts to develop multi-PI investigator proposals. The Signature Center has developed two web resources: the Breast Cancer Prognostics Database (PROGgene) to study prognostic implications of genes of interest in publically available breast cancer databases and PROGmiR, a microRNA database. The PROGgene can be used to study overall, recurrence free and metastasis free survival in large patient series. PROGmiR allows investigators to study the prognostic importance of microRNAs. Both PROGgene and PROGmiR have recently been published and accessed by investigators from >10 countries. The signature center has also devoted considerable efforts in developing tumor tissue resource. Tissue Bank includes a total sample of N = 600 cases with 30% non-Caucasian cases. Currently 460 cases have been assembled into a Tissue Microarray with clinical and follow up data. Expression pattern of AP2γ, a potential marker of breast cancer progression, has been analyzed in a TMA with ~170 cases. The breast cancer signature center has funded four pilot projects and projects for the fourth round of funding are currently under review. Drs. Clark Wells received funding for the project “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”, which resulted in a publication in PNAS. Dr. David Gilley and his group received funding for the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”, which was published in Stem Cell Reports. In the third project, Dr. Theresa Guise is investigating the mechanisms of cancer-associated muscular dysfunction with a future plan for a clinical trial. Drs. Ken Nephew and Milan Radovich received funding to obtain preliminary results for a multi-PI R01 or P01, which will explore genomics and epigenomics of breast cancer using clinical trial materials. Progress made by the signature center was integral in our request to Vera Bradley Foundation for Breast Cancer. This foundation has recently committed $15 million for the breast cancer program, which will be used to develop three themes of research with a focus on personalized therapies to improve outcome in breast cancer patients.
THE INDIANA CENTER FOR BREAST CANCER RESEARCH: PROGRESS REPORT
(Office of the Vice Chancellor for Research, 2013-04-05) Nakshatri, Harikrishna; Sledge, George W., Jr.; Badve, Sunil; Bales, Casey; Gilley, David P.; Goswami, Chirayu; Wells, Clark D.; Guise, Theresa; Ziner, Kim W.
The mission of IUPUI breast cancer center is to address prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts improve resources for breast cancer research and efforts to develop multi-PI investigator proposals. The Signature Center Initiative has developed two web resources: the Breast Cancer Prognostics Database (BCDB) to study prognostic implications of genes of interest in publically available breast cancer databases and PROGmiR, a microRNA database. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. PROGmiR allows investigators to study the prognostic importance of microRNAs. PROGmiR has recently been published and has been accessed by investigators from several countries. The signature center has also devoted considerable efforts in developing tumor tissue resource. Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently 237 cases have been assembled into a Tissue Microarray with clinical and follow up data. The breast cancer center has funded three pilot projects. Drs. Clark Wells, S. Badve, and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David Gilley and his group are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. In the third project, Dr. Theresa Guise will be investigating the mechanisms of cancer-associated cachexia. Several multi-PI proposals are under preparation and one proposal with Drs. Nakshatri and Kathy Miller as PIs is currently under review.
TFAP2C Expression in Breast Cancer - Correlation with Overall Survival Beyond 10 Years of Initial Diagnosis
(Springer, 2015-08) Perkins, Susan M.; Bales, Casey; Vladislav, Tudor; Althouse, Sandra; Miller, Kathy D.; Sandusky, George; Badve, Sunil; Nakshatri, Harikrishna; Department of Surgery, IU School of Medicine
Recurrence and death in a significant number of patients with ERα-positive breast cancer occurs 10–20 years after diagnosis. Prognostic markers for late events have been more elusive. TFAP2C (AP2γ) regulates the expression of ERα, the ERα pioneer factors FOXA1 and GATA3, and controls ERα-dependent transcription. The purpose of this investigation is to determine the long-term prognostic value of TFAP2C. A tissue microarray (TMA) consisting of breast tumors from 451 patients with median follow-up time of 10.3 years was created and tested for the expression of TFAP2C by immunohistochemistry. Wilcoxon Rank-Sum and Kruskal–Wallis tests were used to determine if TFAP2C H-scores correlate with other tumor markers. Cox proportional hazards regression models were used to determine whether TFAP2C H-scores and other tumor markers were related to overall and disease-free survival in univariate and multivariable models. TFPAC2 overexpression did not impact overall survival during the first 10 years after diagnosis, but was associated with a shorter survival after 10 years (HR 3.40, 95 % CI 1.58, 7.30; p value = 0.002). This late divergence persisted in ER-positive (HR 2.86, 95 % CI 1.29, 6.36; p value = 0.01) and endocrine therapy-positive subgroups (HR 4.19, 95 % CI 1.72, 10.23; p value = 0.002). For the ER+ and endocrine therapy subgroup, the HR was 3.82 (95 % CI 1.53, 9.50; p value = 0.004). TFAP2C H-scores were not correlated with other tumor markers or related to disease-free survival. In this hypothesis-generating study, we show that higher TFAP2C scores correlate with poor overall survival after 10 years of diagnosis in ERα-positive and endocrine therapy-treated subgroups.
The Indiana Center for Breast Cancer Research: Progress towards a SPORE Proposal
(Office of the Vice Chancellor for Research, 2012-04-13) Sledge Jr., George W.; Badve, Sunil; Bales, Casey; Gill, Erin M.; Gilley, David P.; Goswami, Chirayu; Wells, Clark D.; Ziner, Kim W.; Nakshatri, Harikrishna
Abstract The Indiana Center for Breast Cancer Research (ICBCR) was funded under the IUPUI Signature Center Initiative in 2010. Its mission is to address the full range of prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts to date towards applying for a National Cancer Institute Specialized Program of Research Excellence (SPORE) in January 2013. The proposed IU Breast Cancer SPORE will include 4-5 individual research projects, 3 cores, developmental research and career development programs. The SPORE Biostatistics and Bioinformatics core has developed the Breast Cancer Prognostics Database (BCDB), an online tool to study prognostic implications of genes of interest in publically available breast cancer databases. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. Supporting the SPORE Biospecimen/Pathology core, the IU Breast Cancer Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently there are N = 333 cases with tissue microarray data and complete clinical data with an additional 200 cases pending tissue confirmation. Dr. Clark D. Wells together with S. Badve and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”, a candidate SPORE individual research project. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David P. Gilley together with N. Kannan, N. Huda, L. Tu, R. Droumeva, R. Brinkman, J. Emerman, S. Abe, and C. Eaves, are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”, a candidate SPORE developmental research project. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. These SPORE projects and cores were discussed at the IUSCC Breast Cancer Program retreat held on 1/13/12. Two additional planning meetings were held on 1/5 and 2/23. A timeline was generated to include final project selection in April, internal review in June, external review in August-September, and draft completion by 12/1, to meet the 1/20/13 NIH receipt deadline.
Ethnicity-dependent and -independent heterogeneity in healthy normal breast hierarchy impacts tumor characterization
(Nature Publishing Group, 2015-08-27) Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima; Department of Surgery, IU School of Medicine
Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations.
The mushroom Ganoderma lucidum suppresses breast-to-lung cancer metastasis through the inhibition of pro-invasive genes.
(Spandidos, 2014-06) Loganathan, Jagadish; Jiang, Jiahua; Smith, Amanda; Jedinak, Andrej; Thyagarajan-Sahu, Anita; Sandusky, George E.; Nakshatri, Harikrishna; Sliva, Daniel; Department of Pathology & Laboratory Medicine, IU School of Medicine
Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice. GLE (100 mg/kg/every other day) was administered to the mice by an oral gavage for 4 weeks, and tumor size was measured using microcalipers. Lung metastases were evaluated by hematoxylin and eosin (H&E) staining. Gene expression in MDA-MB-231 cells was determined by DNA microarray analysis and confirmed by quantitative PCR. Identified genes were silenced by siRNA, and cell migration was determined in Boyden chambers and by wound-healing assay. Although an oral administration of GLE only slightly suppressed the growth of large tumors, the same treatment significantly inhibited the number of breast-to-lung cancer metastases. GLE also downregulated the expression of genes associated with invasive behavior (HRAS, VIL2, S100A4, MCAM, I2PP2A and FN1) in
Cancer impacts microRNA expression, release and function in cardiac and skeletal muscle
(American Association for Cancer Research, 2014-08-15) Chen, Daohong; Goswami, Chirayu P; Burnett, Riesa M; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima; Muller, William; Nakshatri, Harikrishna; Department of Surgery, IU School of Medicine
Circulating microRNAs are emerging as important biomarkers of various diseases including cancer. Intriguingly, circulating levels of several microRNAs are lower in cancer patients compared with healthy individuals. In this study, we tested the hypothesis that a circulating microRNA might serve as a surrogate of the effects of cancer on microRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR-486 is lower in breast cancer patients compared with healthy individuals, and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR-486 were relatively reduced in muscle, where there was elevated expression of the miR-486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD which controls miR-486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro was sufficient to elicit reduced levels of miR-486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated TNFα and four additional cytokines as mediators of miR-486 expression in CM-treated cells. Since miR-486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.
PROGgeneV2: enhancements on the existing database
(Springer (Biomed Central Ltd.), 2014) Goswami, Chirayu Pankaj; Nakshatri, Harikrishna; Department of Surgery, IU School of Medicine
BACKGROUND: We recently published PROGgene, a tool that can be used to study prognostic implications of genes in various cancers. The first version of the tool had several areas for improvement. In this paper we present some major enhancements we have made on the existing tool in the new version, PROGgeneV2. RESULTS: In PROGgeneV2, we have made several modifications to enhance survival analysis capability of the tool. First, we have increased the repository of public studies catalogued in our tool by almost two folds. We have also added additional functionalities to perform survival analysis in a variety of new ways. Survival analysis can now be performed on a) single genes b) multiple genes as a signature, c) ratio of expression of two genes, and d) curated/published gene signatures in new version. Users can now also adjust the survival analysis models for available covariates. Users can study prognostic implications of entire gene signatures in different cancer types, which are searchable by keywords. Also, unique to our tool, in the new version, users will be able to upload and use their own datasets to perform survival analysis on genes of interest. CONCLUSIONS: We believe, like its predecessor, PROGGeneV2 will continue to be useful for the scientific community for formulating research hypotheses and designing mechanistic studies. With added datasets PROGgeneV2 is the most comprehensive survival analysis tool available. PROGgeneV2 is available at http://www.compbio.iupui.edu/proggene.
Using TMAs (Tissue MicroArrays) to Evaluate GLS, GLUL, and CAV 1 Immunostaining in Breast Cancer
(Office of the Vice Chancellor for Research, 2016-04-08) Finnearty, Courtney; Shajahan-Haq, Ayesha; Nakshatri, Hari; Sandusky, George E.
Approximately 1 out of 8 women in the United States will develop invasive breast cancer over the course of their lifetime. Breast cancer has a greater potential of being cured if diagnosed in the earlier phases. We evaluated three well-recognized biomarkers, GLUL, GLS, and Cav 1 (glutamine synthetase, glutaminase, caveolin-1) in 14 TMA (tissue Microarrays). The tissues were normal breast and various subtypes of breast carcinoma by immunohistochemistry (IHC) to determine expression and localization in cancerous tissues in breast carcinoma cases. Approximately 80 to 90 breast biopsies in each of the 14 breast TMA immunostaining were evaluated with the GLUL, GLS, and Cav 1 antibodies. With GLS, immunostaining was seen in most tumor cells (mainly cytoplasm and nucleus) and the stain was clean with no background except in cases that had lymphocytes in the core along with the tumor cells. With GLUL, immunostaining was seen in most tumor cells (mainly cytoplasm and nucleus) and the stain was clean with no background except in cases that had lymphocytes in the core along with the tumor cells. Cav1 was seen only in the endothelial cells in blood vessel walls and some smooth muscle cells in small arterioles in the stroma and surrounding normal ducts, DCIS, and some invasive carcinoma tumor clusters. This information from the immunostains was obtained after analyzing 14 tissue microarrays which is not only time effective but cost effective when analyzing multiple research cases from cancer patients. The data for the three antibodies are currently being analyzed by the biostatistics core group and correlated with the severity of the breast cancer disease with multiple patient demographics.
Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells
(Impact Journals, LLC, 2015-05-20) Burnett, Riesa M.; Craven, Kelly E.; Krishnamurthy, Purna; Goswami, Chirayu P.; Badve, Sunil; Crooks, Peter; Mathews, William P.; Bhat-Nakshatri, Poornima; Nakshatri, Harikrishna; Department of Surgery, IU School of Medicine
Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF-κB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically.

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