Sunil Badve

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https://hdl.handle.net/1805/6682

Sunil Badve's translational research efforts on efficient treatment of breast cancer have a two-pronged approach; developing novel targeted therapies on the one hand and identifying ineffective therapies on the other. His team is studying the individual biological components that culminate in cancer. Gaining a better understanding of these molecular mechanisms will enable identification of key "nodes" in cellular pathways, which can then be targeted by biological agents leading to better diagnosis and effective treatment of breast cancer.

Dr. Badve demonstrated that the FoxA1 protein plays a critical role in determining responses to anti-hormonal therapy IU patent, being licensed. His group has developed a gene signature useful for predicting brain metastasis (IU patent pending) and is currently, with (IU and non-IU) collaborators, trying to dissect the pathways associated with brain metastasis with the hope of preventing and treating this disease. He is also collaborating with IU and Purdue researchers to develop novel methods of detecting and treating breast cancer.

Dr. Badve's practical application of research into information that can be used by local clinicians in treating breast cancer is another example of how IUPUI's faculty members are TRANSLATING their RESEARCH INTO PRACTICE.

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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.
Prognostic Impact of HOTAIR Expression is Restricted to ER-Negative Breast Cancers
(Nature, 2015-03) Gökmen-Polar, Yesim; Vladislav, I. Tudor; Neelamraju, Yaseswini; Janga, Sarath Chandra; Badve, Sunil
Expression of HOX transcript antisense intergenic RNA (HOTAIR), a large intergenic noncoding RNA (lincRNA), has been described as a metastases-associated lincRNA in various cancers including breast, liver and colon cancer cancers. We sought to determine if expression of HOTAIR could be used as a surrogate for assessing nodal metastases and evaluated RNA in situ hybridization (RNA-ISH) assay in a tissue microarray constructed from 133 breast cancer patients. The prognostic value of HOTAIR was further validated in large cohorts using The Cancer Genome Atlas (TCGA) breast cancer subjects. RNA-ISH analysis was successful in 94 cases (17% cases scored 0, 32.9% scored 1, 30.8% scored 2, and 19.1% scored 3). The expression of HOTAIR did not correlate with nodal metastasis regardless of the scoring intensity or with other study parameters (age, tumor size and grade, expression status). Further analysis of TCGA dataset showed that HOTAIR expression was lower in ductal carcinomas but higher in ER-negative tumors. Overexpression of HOTAIR was not associated with nodal metastases or prognosis in ER-positive patients. Its function as a poor prognostic indicator in ER-negative patients was restricted to node-positive patients. HOTAIR appears to be a marker for lymphatic metastases rather than hematogenous metastases in ER-negative patients.
Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options
(2015-05) Ross, Jeffrey S.; Badve, Sunil; Wang, Kai; Sheehan, Christine E.; Boguniewicz, Ann B.; Otto, Geoff A.; Yelensky, Roman; Lipson, Doron; Ali, Siraj; Morosini, Deborah; Chliemlecki, Juliann; Elvin, Julia A.; Miller, Vincent A.; Stephens, Philip J.; Department of Pathology and Laboratory Medicine, IU School of Medicine
Context.— Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy. Objective.— To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC. Design.— Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage. Results.— The 20 patients with MPBC had a median age of 62 years (range, 42–86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1–11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing–based copy-number assessment. Conclusions.— Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.
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.
The Birth of an Adenoid Cystic Carcinoma
(Sage, 2015-02) Fusco, Nicola; Guerini-Rocco, Elena; Schultheis, Anne M.; Badve, Sunil S.; Reis-Filho, Jorge S.; Weigelt, Britta; Department of Pathology and Laboratory Medicine, IU School of Medicine
Adenoid cystic carcinoma is a rare malignancy of exocrine glands defined by the presence of a dual population of cells (epithelial and myoepithelial cells) organized in varying combinations of cribriform, tubular, and solid patterns.1,2 This neoplasm most frequently originates in the salivary glands; however, it can also occur in other anatomical sites, including the breast.1,3 More than 90% of adenoid cystic carcinomas of the breast harbor the recurrent translocation t(6;9), resulting in the MYB-NFIB fusion gene, which leads to MYB overexpression.4 Adenoid cystic carcinoma in situ has been described in the breast; however, its identifica-tion is not trivial.3 Here, we illustrate an in situ adenoid cystic carcinoma partially involving a mammary duct in a 68-year-old woman with primary adenoid cystic carci-noma of the right breast. The double population of cells composing this intraductal lesion can be appreciated by its immunohistochemical profile (Figure 1). Given that the neoplastic cells of the in situ lesion already express MYB, our findings are consistent with the notion that MYB overexpression is an early event in the tumorigen-esis of adenoid cystic carcinomas.4,5
Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer
(Nature Publishing Group, 2015-05) Gökmen-Polar, Yesim; Neelamraju, Yaseswini; Goswami, Chirayu P.; Gu, Xiaoping; Nallamothu, Gouthami; Janga, Sarath Chandra; Badve, Sunil; Department of Pathology and Laboratory Medicine, IU School of Medicine
De novo or acquired resistance to endocrine therapy limits its utility in a significant number of estrogen receptor-positive (ER-positive) breast cancers. It is crucial to identify novel targets for therapeutic intervention and improve the success of endocrine therapies. Splicing factor 3b, subunit 1 (SF3B1) mutations are described in luminal breast cancer albeit in low frequency. In this study, we evaluated the role of SF3B1 and SF3B3, critical parts of the SF3b splicing complex, in ER-positive endocrine resistance. To ascertain the role of SF3B1/SF3B3 in endocrine resistance, their expression levels were evaluated in ER-positive/endocrine-resistant cell lines (MCF-7/LCC2 and MCF-7/LCC9) using a real-time quantitative reverse transcription PCR (qRT-PCR). To further determine their clinical relevance, expression analysis was performed in a cohort of 60 paraffin-embedded ER-positive, node-negative breast carcinomas with low, intermediate, and high Oncotype DX recurrence scores. Expression levels of SF3B1 and SF3B3 and their prognostic value were validated in large cohorts using publicly available gene expression data sets including The Cancer Genome Atlas. SF3B1 and SF3B3 levels were significantly increased in ERα-positive cells with acquired tamoxifen (MCF-7/LCC2; both P<0.0002) and fulvestrant/tamoxifen resistance (MCF-7/LCC9; P=0.008 for SF3B1 and P=0.0006 for SF3B3). Expression levels of both MCF-7/LCC2 and MCF-7/LCC9 were not affected by additional treatments with E2 and/or tamoxifen. Furthermore, qRT-PCR analysis confirmed that SF3B3 expression is significantly upregulated in Oncotype DX high-risk groups when compared with low risk (P=0.019). Similarly, in publicly available breast cancer gene expression data sets, overexpression of SF3B3, but not SF3B1, was significantly correlated with overall survival. Furthermore, the correlation was significant in ER-positive, but not in ER-negative tumors.
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.
Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing
(Springer, 2014-01) Radovich, Milan; Clare, Susan E.; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A.; Solzak, Jeffrey P.; Kassem, Nawal; Mathieson, Theresa; V. Storniolo, Anna Maria; Rufenbarger, Connie; Lillemoe, Heather A.; Blosser, Rachel J.; Choi, Mi Ran; Sauder, Candice A.; Doxey, Diane; Henry, Jill E.; Hilligoss, Eric E.; Sakarya, Onur; Hyland, Fiona C.; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W.; Schneider, Bryan P.; Department of Surgery, IU School of Medicine
Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.
Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients
(Springer US, 2015-03) Duchnowska, Renata; Jassem, Jacek; Goswami, Chirayu Pankaj; Dundar, Murat; Gökmen-Polar, Yesim; Li, Lang; Woditschka, Stephan; Biernat, Wojciech; Sosińska-Mielcarek, Katarzyna; Czartoryska-Arłukowicz, Bogumiła; Radecka, Barbara; Tomasevic, Zorica; Stępniak, Piotr; Wojdan, Konrad; Sledge, George W. Jr.; Steeg, Patricia S.; Badve, Sunil; Department of Medical & Molecular Genetics, IU School of Medicine
The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4–22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5–25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4–10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0–100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6–16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.

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