Browsing by Author "Clare, Susan E."

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    Author Correction: Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer
    (Springer Nature, 2023-03-13) Yadav, Shivangi; Virk, Ranya; Chung, Carolina H.; Bustamante Eduardo, Mariana; VanDerway, David; Chen, Duojiao; Burdett, Kirsten; Gao, Hongyu; Zeng, Zexian; Ranjan, Manish; Cottone, Gannon; Xuei, Xiaoling; Chandrasekaran, Sriram; Backman, Vadim; Chatterton, Robert; Khan, Seema Ahsan; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    Correction to: npj Breast Cancer 10.1038/s41523-022-00422-0, published online 04 May 2022 In this article, funding from the National Institutes of Health (award number R01CA228272) was inadvertently omitted. The original article has been corrected.
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    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.
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    Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse
    (Springer, 2012) Choi, Mi-Ran; Bardhan, Rizia; Stanton-Maxey, Katie J.; Badve, Sunil; Nakshatri, Harikrishna; Stantz, Keith M.; Cao, Ning; Halas, Naomi J.; Clare, Susan E.
    As systemic cancer therapies improve and are able to control metastatic disease outside the central nervous system, the brain is increasingly the first site of relapse. The blood–brain barrier (BBB) represents a major challenge to the delivery of therapeutics to the brain. Macrophages originating from circulating monocytes are able to infiltrate brain metastases while the BBB is intact. Here, we show that this ability can be exploited to deliver both diagnostic and therapeutic nanoparticles specifically to experimental brain metastases of breast cancer.
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    Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer
    (Springer Nature, 2022-05-04) Yadav, Shivangi; Virk, Ranya; Chung, Carolina H.; Bustamante Eduardo, Mariana; VanDerway, David; Chen, Duojiao; Burdett, Kirsten; Gao, Hongyu; Zeng, Zexian; Ranjan, Manish; Cottone, Gannon; Xuei, Xiaoling; Chandrasekaran, Sriram; Backman, Vadim; Chatterton, Robert; Khan, Seema Ahsan; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A and MCF-12A cells, and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility, and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.
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    Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer
    (Wiley, 2013-06) Wei, Siwei; Liu, Lingyan; Zhang, Jian; Bowers, Jeremiah; Gowda, G.A. Nagana; Seeger, Harald; Fehm, Tanja; Neubauer, Hans J.; Vogel, Ulrich; Clare, Susan E.; Raftery, Daniel; Surgery, School of Medicine
    Breast cancer is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. As an example, only some women will benefit from chemotherapy. Identifying patients who will respond to chemotherapy and thereby improve their long‐term survival has important implications to treatment protocols and outcomes, while identifying non responders may enable these patients to avail themselves of other investigational approaches or other potentially effective treatments. In this study, serum metabolite profiling was performed to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy for breast cancer. Metabolic profiles of serum from patients with complete (n = 8), partial (n = 14) and no response (n = 6) to chemotherapy were studied using a combination of nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography–mass spectrometry (LC–MS) and statistical analysis methods. The concentrations of four metabolites, three (threonine, isoleucine, glutamine) from NMR and one (linolenic acid) from LC–MS were significantly different when comparing response to chemotherapy. A prediction model developed by combining NMR and MS derived metabolites correctly identified 80% of the patients whose tumors did not show complete response to chemotherapy. These results show promise for larger studies that could result in more personalized treatment protocols for breast cancer patients., ► Metabolomics differentiates response to neoadjuvant breast cancer chemotherapy.► Four serum metabolites are found to correlate with response to chemotherapy.► A 4‐metabolite model identifies 80% of the patients not showing complete response.► Additional studies on larger patient cohorts are needed to validate the findings.
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    Motivations for contralateral prophylactic mastectomy as a function of socioeconomic status
    (BioMed Central, 2017-02-01) Baptiste, Dadrie F.; MacGeorge, Erina L.; Venetis, Maria K.; Mouton, Ashton; Friley, L. Brooke; Pastor, Rebekah; Hatten, Kristen; Lagoo, Janaka; Clare, Susan E.; Bowling, Monet W.; Department of Surgery, IU School of Medicine
    BACKGROUND: Despite no demonstrated survival advantage for women at average risk of breast cancer, rates of contralateral prophylactic mastectomy (CPM) continue to increase. Research reveals women with higher socioeconomic status (SES) are more likely to select CPM. This study examines how indicators of SES, age, and disease severity affect CPM motivations. METHODS: Patients (N = 113) who underwent CPM at four Indiana University affiliated hospitals completed telephone interviews in 2013. Participants answered questions about 11 CPM motivations and provided demographic information. Responses to motivation items were factor analyzed, resulting in 4 motivational factors: reducing long-term risk, symmetry, avoiding future medical visits, and avoiding treatments. RESULTS: Across demographic differences, reducing long-term risk was the strongest CPM motivation. Lower income predicted stronger motivation to reduce long-term risk and avoid treatment. Older participants were more motivated to avoid treatment; younger and more-educated patients were more concerned about symmetry. Greater severity of diagnosis predicted avoiding treatments. CONCLUSIONS: Reducing long-term risk is the primary motivation across groups, but there are also notable differences as a function of age, education, income, and disease severity. To stop the trend of increasing CPM, physicians must tailor patient counseling to address motivations that are consistent across patient populations and those that vary between populations.
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    Next-generation transcriptome sequencing of the premenopausal breast epithelium using specimens from a normal human breast tissue bank
    (Biomed Central, 2014) Pardo, Ivanesa; Lillemoe, Heather A.; Blosser, Rachel J.; Choi, MiRan; Sauder, Candice A. M.; Doxey, Diane K.; Mathieson, Theresa; Hancock, Bradley A.; Baptiste, Dadrie; Atale, Rutuja; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Storniolo, Anna Maria V.; Zheng, Faye; Doerge, R. W.; Liu, Yunlong; Badve, Sunil S.; Radovich, Milan; Clare, Susan E.; Pathology and Laboratory Medicine, School of Medicine
    Introduction Our efforts to prevent and treat breast cancer are significantly impeded by a lack of knowledge of the biology and developmental genetics of the normal mammary gland. In order to provide the specimens that will facilitate such an understanding, The Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center (KTB) was established. The KTB is, to our knowledge, the only biorepository in the world prospectively established to collect normal, healthy breast tissue from volunteer donors. As a first initiative toward a molecular understanding of the biology and developmental genetics of the normal mammary gland, the effect of the menstrual cycle and hormonal contraceptives on DNA expression in the normal breast epithelium was examined. Methods Using normal breast tissue from 20 premenopausal donors to KTB, the changes in the mRNA of the normal breast epithelium as a function of phase of the menstrual cycle and hormonal contraception were assayed using next-generation whole transcriptome sequencing (RNA-Seq). Results In total, 255 genes representing 1.4% of all genes were deemed to have statistically significant differential expression between the two phases of the menstrual cycle. The overwhelming majority (221; 87%) of the genes have higher expression during the luteal phase. These data provide important insights into the processes occurring during each phase of the menstrual cycle. There was only a single gene significantly differentially expressed when comparing the epithelium of women using hormonal contraception to those in the luteal phase. Conclusions We have taken advantage of a unique research resource, the KTB, to complete the first-ever next-generation transcriptome sequencing of the epithelial compartment of 20 normal human breast specimens. This work has produced a comprehensive catalog of the differences in the expression of protein-coding genes as a function of the phase of the menstrual cycle. These data constitute the beginning of a reference data set of the normal mammary gland, which can be consulted for comparison with data developed from malignant specimens, or to mine the effects of the hormonal flux that occurs during the menstrual cycle.
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    Phenotypic plasticity in normal breast derived epithelial cells
    (Biomed Central, 2014) Sauder, Candice A. M.; Koziel, Jillian E.; Choi, MiRan; Fox, Melanie J.; Grimes, Brenda R.; Badve, Sunil S.; Blosser, Rachel J.; Radovich, Milan; Lam, Christina C.; Vaughan, Melville B.; Herbert, Brittney-Shea; Clare, Susan E.; Pathology and Laboratory Medicine, School of Medicine
    Background Normal, healthy human breast tissue from a variety of volunteer donors has become available for research thanks to the establishment of the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center (KTB). Multiple epithelial (K-HME) and stromal cells (K-HMS) were established from the donated tissue. Explant culture was utilized to isolate the cells from pieces of breast tissue. Selective media and trypsinization were employed to select either epithelial cells or stromal cells. The primary, non-transformed epithelial cells, the focus of this study, were characterized by immunohistochemistry, flow cytometry, and in vitro cell culture. Results All of the primary, non-transformed epithelial cells tested have the ability to differentiate in vitro into a variety of cell types when plated in or on biologic matrices. Cells identified include stratified squamous epithelial, osteoclasts, chondrocytes, adipocytes, neural progenitors/neurons, immature muscle and melanocytes. The cells also express markers of embryonic stem cells. Conclusions The cell culture conditions employed select an epithelial cell that is pluri/multipotent. The plasticity of the epithelial cells developed mimics that seen in metaplastic carcinoma of the breast (MCB), a subtype of triple negative breast cancer; and may provide clues to the origin of this particularly aggressive type of breast cancer. The KTB is a unique biorepository, and the normal breast epithelial cells isolated from donated tissue have significant potential as new research tools.
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    Social Network, Surgeon, and Media Influence on the Decision to Undergo Contralateral Prophylactic Mastectomy
    (Lippincott, Williams & Wilkins, 2018-06) Venetis, Maria K.; MacGeorge, Erina L.; Baptiste, Dadrie F.; Mouton, Ashton; Friley, Lorin B.; Pastor, Rebekah; Hatten, Kristen; Lagoo, Janaka; Bowling, Monet W.; Clare, Susan E.; Surgery, School of Medicine
    OBJECTIVES: The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade. The current study was designed to examine social network, surgeon, and media influence on patients' CPM decision-making, examining not only who influenced the decision, and to what extent, but also the type of influence exerted. METHODS: Patients (N=113) who underwent CPM at 4 Indiana University-affiliated hospitals between 2008 and 2012 completed structured telephone interviews in 2013. Questions addressed the involvement and influence of the social network (family, friends, and nonsurgeon health professionals), surgeon, and media on the CPM decision. RESULTS: Spouses, children, family, friends, and health professionals were reported as exerting a meaningful degree of influence on patients' decisions, largely in ways that were positive or neutral toward CPM. Most surgeons were regarded as providing options rather than encouraging or discouraging CPM. Media influence was present, but limited. CONCLUSIONS: Patients who choose CPM do so with influence and support from members of their social networks. Reversing the increasing choice of CPM will require educating these influential others, which can be accomplished by encouraging patients to include them in clinical consultations, and by providing patients with educational materials that can be shared with their social networks. Surgeons need to be perceived as having an opinion, specifically that CPM should be reserved for those patients for whom it is medically indicated.
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    Somatic genetic aberrations in benign breast disease and the risk of subsequent breast cancer
    (Nature, 2020-06-12) Zeng, Zexian; Vo, Andy; Li, Xiaoyu; Shidfar, Ali; Saldana, Paulette; Blanco, Luis; Xuei, Xiaoling; Luo, Yuan; Khan, Seema A.; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    It is largely unknown how the development of breast cancer (BC) is transduced by somatic genetic alterations in the benign breast. Since benign breast disease is an established risk factor for BC, we established a case-control study of women with a history of benign breast biopsy (BBB). Cases developed BC at least one year after BBB and controls did not develop BC over an average of 17 years following BBB. 135 cases were matched to 69 controls by age and type of benign change: non-proliferative or proliferation without atypia (PDWA). Whole-exome sequencing (WES) was performed for the BBB. Germline DNA (available from n = 26 participants) was utilized to develop a mutation-calling pipeline, to allow differentiation of somatic from germline variants. Among the 204 subjects, two known mutational signatures were identified, along with a currently uncatalogued signature that was significantly associated with triple negative BC (TNBC) (p = 0.007). The uncatalogued mutational signature was validated in 109 TNBCs from TCGA (p = 0.001). Compared to non-proliferative samples, PDWA harbors more abundant mutations at PIK3CA pH1047R (p < 0.001). Among the 26 BBB whose somatic copy number variation could be assessed, deletion of MLH3 is significantly associated with the mismatch repair mutational signature (p < 0.001). Matched BBB-cancer pairs were available for ten cases; several mutations were shared between BBB and cancers. This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed.