Lester and Sue Smith Breast Center

Medicine Lodge, United States

Lester and Sue Smith Breast Center

Medicine Lodge, United States

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News Article | April 21, 2017
Site: www.eurekalert.org

A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. The study appears in Nature Communications. "For a number of breast cancer patients, the problem is metastasis -- the dissemination of breast tumor cells to other organs -- after the primary tumor has been eliminated," said corresponding author Dr. Xiang Zhang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor. "Metastases, however, tend to respond differently than the primary tumor to the treatment in part due to residing in a different organ with a different microenvironment." Until now, there has not been an effective experimental platform to study metastatic tumors in their new microenvironment. "We have created an experimental system in which we can mimic the interactions between cancer cells and bone cells, as bone is the place where breast cancer, and many other cancers too, disseminates most frequently," said Zhang, who also is a McNair Scholar at Baylor. "We have developed a system that allows us to test many different drug responses simultaneously to discover the therapy that can selectively act on metastatic cancer cells and minimize the effect on the bone." To mimic the interactions between metastatic breast cancer cells and bone cells in a living system in the lab, Zhang and his colleagues developed a bone metastasis model, called bone-in culture array, by fragmenting mouse bones that already contain breast cancer cells. The scientists determined that the bone-in culture maintains the microenvironmental characteristics of bone metastasis in living animal models, and the cancer cells maintain the gene expression profile, the growth pattern and their response to therapies. Using the bone-in model, the researchers determined that the drug danusertib preferentially inhibits bone metastasis. They also found that other drugs stimulate the growth of slow-growing cancer cells in the bone. In addition to determining the effect of drugs in the growth of metastasis in bone, the bone-in culture can be used to investigate mechanisms involved in bone colonization by cancer cells. "We think that this new system has the potential to be applied not only to breast cancer but to other cancers that also metastasize to the bone," Zhang said. "This technique can be scaled up to larger sample sizes, which would help accelerate the process of discovering metastatic cancer treatments. We have already found a few interesting drugs. We will keep looking for more and focus on those that are most promising." In the future, the scientists expect to develop this platform into a standardized system that can be used in the clinic to find specific drugs that can better treat metastatic cancer. Other contributors to this work include Hai Wang, Lin Tian, Amit Goldstein, Jun Liu, Hin-Ching Lo, Kuanwei Sheng, Thomas Welte, Stephen T. C. Wong, Zbigniew Gugala, Fabio Stossi, Chenghang Zong, Zonghai Li and Michael A. Mancini. The authors are affiliated with one or more of the following institutions: Baylor, Shanghai Jiao Tong University School of Medicine, Weill Cornell Medical College, Houston Methodist Hospital and the University of Texas Medical Branch, Galveston. Financial support was provided by the U.S. Department of Defense (DAMD W81XWH-16-1-0073, DAMD W81XWH-13-1-0296), the National Cancer Institute (CA183878), the Breast Cancer Research Foundation, Susan G. Komen (CCR14298445), and the McNair Medical Institute. This work was also made possible by the CyVerse Collaborative, funded by the National Science Foundation (No. DBI-0735191), the Integrated Microscopy Core at Baylor College of Medicine with funding from the National Institutes of Health (HD007495, DK56338, and CA125123), the Pathology Core of the Lester and Sue Smith Breast Center, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.


News Article | April 21, 2017
Site: www.rdmag.com

A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. The study appears in Nature Communications. "For a number of breast cancer patients, the problem is metastasis -- the dissemination of breast tumor cells to other organs -- after the primary tumor has been eliminated," said corresponding author Dr. Xiang Zhang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor. "Metastases, however, tend to respond differently than the primary tumor to the treatment in part due to residing in a different organ with a different microenvironment." Until now, there has not been an effective experimental platform to study metastatic tumors in their new microenvironment. "We have created an experimental system in which we can mimic the interactions between cancer cells and bone cells, as bone is the place where breast cancer, and many other cancers too, disseminates most frequently," said Zhang, who also is a McNair Scholar at Baylor. "We have developed a system that allows us to test many different drug responses simultaneously to discover the therapy that can selectively act on metastatic cancer cells and minimize the effect on the bone." To mimic the interactions between metastatic breast cancer cells and bone cells in a living system in the lab, Zhang and his colleagues developed a bone metastasis model, called bone-in culture array, by fragmenting mouse bones that already contain breast cancer cells. The scientists determined that the bone-in culture maintains the microenvironmental characteristics of bone metastasis in living animal models, and the cancer cells maintain the gene expression profile, the growth pattern and their response to therapies. Using the bone-in model, the researchers determined that the drug danusertib preferentially inhibits bone metastasis. They also found that other drugs stimulate the growth of slow-growing cancer cells in the bone. In addition to determining the effect of drugs in the growth of metastasis in bone, the bone-in culture can be used to investigate mechanisms involved in bone colonization by cancer cells. "We think that this new system has the potential to be applied not only to breast cancer but to other cancers that also metastasize to the bone," Zhang said. "This technique can be scaled up to larger sample sizes, which would help accelerate the process of discovering metastatic cancer treatments. We have already found a few interesting drugs. We will keep looking for more and focus on those that are most promising." In the future, the scientists expect to develop this platform into a standardized system that can be used in the clinic to find specific drugs that can better treat metastatic cancer.


News Article | April 21, 2017
Site: www.rdmag.com

A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. The study appears in Nature Communications. "For a number of breast cancer patients, the problem is metastasis -- the dissemination of breast tumor cells to other organs -- after the primary tumor has been eliminated," said corresponding author Dr. Xiang Zhang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor. "Metastases, however, tend to respond differently than the primary tumor to the treatment in part due to residing in a different organ with a different microenvironment." Until now, there has not been an effective experimental platform to study metastatic tumors in their new microenvironment. "We have created an experimental system in which we can mimic the interactions between cancer cells and bone cells, as bone is the place where breast cancer, and many other cancers too, disseminates most frequently," said Zhang, who also is a McNair Scholar at Baylor. "We have developed a system that allows us to test many different drug responses simultaneously to discover the therapy that can selectively act on metastatic cancer cells and minimize the effect on the bone." To mimic the interactions between metastatic breast cancer cells and bone cells in a living system in the lab, Zhang and his colleagues developed a bone metastasis model, called bone-in culture array, by fragmenting mouse bones that already contain breast cancer cells. The scientists determined that the bone-in culture maintains the microenvironmental characteristics of bone metastasis in living animal models, and the cancer cells maintain the gene expression profile, the growth pattern and their response to therapies. Using the bone-in model, the researchers determined that the drug danusertib preferentially inhibits bone metastasis. They also found that other drugs stimulate the growth of slow-growing cancer cells in the bone. In addition to determining the effect of drugs in the growth of metastasis in bone, the bone-in culture can be used to investigate mechanisms involved in bone colonization by cancer cells. "We think that this new system has the potential to be applied not only to breast cancer but to other cancers that also metastasize to the bone," Zhang said. "This technique can be scaled up to larger sample sizes, which would help accelerate the process of discovering metastatic cancer treatments. We have already found a few interesting drugs. We will keep looking for more and focus on those that are most promising." In the future, the scientists expect to develop this platform into a standardized system that can be used in the clinic to find specific drugs that can better treat metastatic cancer.


Welte T.,Lester and Sue Smith Breast Center | Welte T.,Dan ncan Cancer Center | Welte T.,Cellular One | Welte T.,Diana Helis Henry Medical Research Foundation | And 7 more authors.
Journal of Mammary Gland Biology and Neoplasia | Year: 2015

In breast cancer, the most frequent site of metastasis is bone. Disseminated tumor cells (DTCs) can be detected in the bone marrow of patients by their expression of epithelial or oncogenic markers [1], and the presence and frequency of these DTCs are associated with poor prognosis. However, many of the details behind this process remain elusive, including the biological properties and fates of these apparently indolent cancer cells. To provide pre-clinical models of DTCs, we have developed a procedure that allows for controlled and enhanced delivery of tumor cells to the bone in animal experiments via injection into the iliac artery of the hind limb [2]. To our surprise, we found that most cancer cells became integrated into the solid bone matrix shortly after arriving in the bone, and only a minority can be flushed out with the bone marrow. Here we describe a method that helps to retrieve DTCs homing to the bone in which we achieve an improved recovery of those tumor cells closely associated with the bone microenvironment. In our view it is especially important to analyze these tumor cell subpopulations, as they may take full advantage of growth-, survival- and immune-protective signals provided by neighbor cells. We also show a pilot study on how this approach may be applied to the analysis of cancer dormancy. Our study suggests that the detection and retrieval of DTCs in clinical studies are incomplete because they are conducted exclusively with bone marrow aspirates. © 2015, Springer Science+Business Media New York.


PubMed | University of British Columbia, University of Washington and Lester and Sue Smith Breast Center
Type: Journal Article | Journal: The Journal of molecular diagnostics : JMD | Year: 2016

Fibroblast growth factor receptor 1 (FGFR1) amplification drives poor prognosis and is an emerging therapeutic target. We sought to construct a multigene mRNA expression signature to efficiently identify FGFR1-amplified estrogen receptor-positive (ER


Litzenburger B.C.,Lester and Sue Smith Breast Center | Litzenburger B.C.,RWTH Aachen | Creighton C.J.,Baylor College of Medicine | Tsimelzon A.,Lester and Sue Smith Breast Center | And 17 more authors.
Clinical Cancer Research | Year: 2011

Purpose: We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti-IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti-IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807. Experimental Design: An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti-IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy. Results: The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti-IGF-IR therapies. The IGF signature was present in triplenegative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. Conclusions: These studies provide a clear biological rationale to test anti-IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC. © 2011 American Association for Cancer Research.


Barone I.,Lester and Sue Smith Breast Center | Barone I.,Centro Sanitario | Barone I.,University of Calabria | Brusco L.,Lester and Sue Smith Breast Center | And 12 more authors.
Journal of the National Cancer Institute | Year: 2011

BackgroundEstrogen receptor (ER) α is a successful therapeutic target in breast cancer, but patients eventually develop resistance to antiestrogens such as tamoxifen.MethodsTo identify genes whose expression was associated with the development of tamoxifen resistance and metastasis, we used microarrays to compare gene expression in four primary tumors from tamoxifen-treated patients whose breast cancers did not recur vs five metastatic tumors from patients whose cancers progressed during adjuvant tamoxifen treatment. Because Rho guanine dissociation inhibitor (GDI) α was underexpressed in the tamoxifen-resistant group, we stably transfected ERα-positive MCF-7 breast cancer cells with a plasmid encoding a short hairpin (sh) RNA to silence Rho GDIα expression. We used immunoblots and transcription assays to examine the role of Rho GDIα in ER-related signaling and growth of cells in vitro and as xenografts in treated nude mice (n = 8-9 per group) to examine the effects of Rho GDIα blockade on hormone responsiveness and metastatic behavior. The time to tumor tripling as the time in weeks from randomization to a threefold increase in total tumor volume over baseline was examined in treated mice. The associations of Rho GDIα and MTA2 levels with tamoxifen resistance were examined in microarray data from patients. All statistical tests were two-sided.ResultsRho GDIα was expressed at lower levels in ERα-positive tumors that recurred during tamoxifen treatment than in ERα-positive tamoxifen-sensitive primary tumors. MCF-7 breast cancer cells in which Rho GDIα expression had been silenced were tamoxifen-resistant, had increased Rho GTPase and p21-activated kinase 1 activity, increased phosphorylation of ERα at serine 305, and enhanced tamoxifen-induced ERα transcriptional activity compared with control cells. MCF-7 cells in which Rho GDIα expression was silenced metastasized with high frequency when grown as tumor xenografts. When mice were treated with estrogen or estrogen withdrawal, tripling times for xenografts from cells with Rho GDIα silencing were similar to those from vector-containing control cells; however, tripling times were statistically significantly faster than control when mice were treated with tamoxifen (median tripling time for tumors with Rho GDIα small interfering RNA = 2.34 weeks; for control tumors = not reached, hazard ratio = 4.13, 95% confidence interval = 1.07 to 15.96, P =. 040 [adjusted for multiple comparisons, P =. 119]). Levels of the metastasis-associated protein MTA2 were also increased upon Rho GDIα silencing, and combined Rho GDIα and MTA2 levels were associated with recurrence in 250 tamoxifen-treated patients.ConclusionLoss of Rho GDIα enhances metastasis and resistance to tamoxifen via effects on both ERα and MTA2 in models of ERα-positive breast cancer and in tumors of tamoxifen-treated patients. © 2011 The Author.


Gutierrez C.,Lester and Sue Smith Breast Center | Schiff R.,Baylor College of Medicine
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-HER2 is a membrane tyrosine kinase and oncogene that is overexpressed and gene amplified in about 20% of breast cancers. When activated it provides the cell with potent proliferative and antiapoptosis signals and it is the major driver of tumor development and progression for this subset of breast cancer. When shown to be overexpressed or amplified by appropriate methods, HER2 is a valuable treatment target. Objectives.-To review the basic biology of the HER2 signaling network, to discuss various approved methods for its detection in clinical specimens, and to describe the impressive results of therapies targeting HER2. Data Sources.-Selected literature searchable on PubMed as well as older studies revealed by the literature review were reviewed. Conclusion.-HER2 is an important member of a complex signaling network and when gene amplified, it results in an aggressive subtype of breast cancer. Patients with tumors found to overexpress HER2 protein or to be amplified for the gene are candidates for therapy that significantly reduces mortality.


Hammerich-Hille S.,Lester and Sue Smith Breast Center | Kaipparettu B.A.,Lester and Sue Smith Breast Center | Tsimelzon A.,Lester and Sue Smith Breast Center | Creighton C.J.,Lester and Sue Smith Breast Center | And 6 more authors.
Journal of Biological Chemistry | Year: 2010

The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system.Asubsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Lester and Sue Smith Breast Center
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2010

The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system. A subsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes.

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