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The promise of microarrays in the management and treatment of breast cancer
Jenny C Chang, Susan G Hilsenbeck, Suzanne AW Fuqua
Breast Cancer Research , 2005, DOI: 10.1186/bcr1018
Abstract: Mortality from breast cancer results from the ability of some tumors to metastasize to distant sites. Selecting patients with micrometastases at diagnosis is crucial for clinicians in deciding who should and who should not receive toxic and expensive adjuvant chemotherapy to eradicate these metastatic cells. Although many individual biomarkers were originally attractive, over the years most have failed to become clinically useful. In addition, the management of breast cancer has changed, with most node-negative patients now undergoing systemic adjuvant therapy because we cannot precisely determine an individual's risk of recurrence. A majority of node-negative patients are being unnecessarily overtreated because if they were left systemically untreated, only about 25% of node-negative patients would ever develop recurrence. There is therefore a crucial need to identify patients with a sufficiently low risk of breast cancer recurrence to avoid further treatment. In addition, in patients at risk of recurrence and in need of therapy, optimal therapeutic selection is an increasingly important objective. Recent developments in applying microarray technologies to breast tumor samples suggest that these new techniques might provide for the transition of molecular biological discoveries to clinical application, and will generate clinically useful genomic profiles that more accurately predict long-term outcome for individual breast cancer patients.Until recently, evaluations of prognostic and predictive factors have considered one factor at a time or have used small panels of markers. However, with the advent of new genomic technologies such as microarrays capable of simultaneously measuring thousands of genes or gene products, we are beginning to construct molecular fingerprints of individual tumors so that accurate prognostic and predictive assessments of each cancer can be made. Clinicians might one day base clinical management on each woman's personal prognosis and predi
The role of single nucleotide polymorphisms in breast cancer metastasis
James M Rae, Todd C Skaar, Susan G Hilsenbeck, Steffi Oesterreich
Breast Cancer Research , 2008, DOI: 10.1186/bcr1842
Abstract: Modern genetics has been applied to many aspects of breast cancer. For example, it is well established that inherited mutations in BCRA1 and BCRA2 can predispose women to this disease, as well as to ovarian cancer [1]. Changes in other genes, such as p53, PTEN, or CHEK2, are also associated with increased risk of breast cancer. Recent genome-wide association studies have led to the identification of numerous polymorphisms associated with increased risk for breast cancer, with FGFR2 being one of the top candidate genes [2,3]. Also, numerous ongoing studies are being carried out to understand whether there is a heritable genetic contribution to therapeutic responses in breast cancer patients [4]. Because of the importance of metastasis in the prognosis of breast cancer patients, it is important to determine whether germ line polymorphisms also play a role in breast cancer metastasis. Indeed, there is a paucity of data from microarray and other studies to fully explain breast cancer metastasis from tumor somatic cell evolution, thus opening the question of whether germline polymorphisms could contribute to breast cancer metastasis.Recent studies in mice indicate that inherited genetic backgrounds can influence metastatic potential. The elucidation of the causal genetic variants in these models may lead to the identification of important metastasis genes and heritable genetic variants that predispose humans to breast cancer metastasis. Using the MMTV-PyMT transgenic mouse model, which develops mammary tumors with 100% penetrance, Hunter and colleagues [5] have shown that the incidence of pulmonary metastasis was influenced by the mouse genetic background. They found that the AKR and FVB stains show high metastatic efficiency, while two others (DBA and NZB) show low rates of metastasis. Quantitative trait genetic mapping analysis identified a probable metastasis efficiency locus (Mtes1) on mouse chromosome 19 in a 10 Mb region orthologous to human chromosome 11q12-13. Al
Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer
Sangjun Lee, Syed K Mohsin, Sufeng Mao, Susan G Hilsenbeck, Dan Medina, D Craig Allred
Breast Cancer Research , 2005, DOI: 10.1186/bcr1367
Abstract: Proliferation (Ki67 antigen), ER-α, and PR were assessed by immunohistochemistry, apoptosis using the TUNEL (terminal transferase-mediated dUTP nick end-labeling) assay, and nuclear colocalization of ER-α and Ki67 by dual-labeled immunofluorescence in HELUs and adjacent TDLUs (n = 100–584, depending on the factor) from 324 breasts. All factors were quantified under direct microscopic visualization. ER-α/PR expression was semiquantified by estimating the proportion of positive cells (0 = none, 1 = <1/100, 2 = 1/100 to 1/10, 3 = 1/10 to 1/3, 4 = 1/3 to 2/3, and 5 = >2/3). Ki67, TUNEL, and colocalization of ER-α and Ki67 were scored by absolute counting (%positive).ER-α and PR expression were significantly elevated in HELUs versus adjacent TLDUs (average score: 4.5 versus 3.1 and 3.5 versus 2.1; P < 0.0001). Proliferation was also significantly higher in HELUs versus TDLUs (average 6.3% versus 2.0%; P < 0.0001). In contrast, apoptosis was significantly lower in HELUs versus TDLUs (average 0.61% versus 0.22%; P < 0.0001). Changes in proliferation and receptor expression were similar between premenopausal and postmenopausal TDLUs and HELUs, suggesting that hyperplastic cells remain responsive to regulation by estrogen. The proportion of ER-positive/proliferating cells was much higher in HELUs than TDLUs (27.6% vs. 4.9%; P < .0001).Development of HELUs is associated with increased proliferation and decreased cell death relative to normal cells. ER-α and PR are highly elevated in HELUs, which may contribute to the hyperplasia because they mediate hormonal regulation of growth. An understanding of the fundamental causes of increased levels of receptors and growth may lead to new strategies to prevent breast cancer.Enlarged terminal duct lobular units (TDLUs) are common alterations in the adult female human breast. They are typically lined by crowded columnar epithelial cells, and the degree of enlargement can be substantial (Fig. 1). They have been discussed intermittently
Meta-analysis of multiple microarray datasets reveals a common gene signature of metastasis in solid tumors
Marla H Daves, Susan G Hilsenbeck, Ching C Lau, Tsz-Kwong Man
BMC Medical Genomics , 2011, DOI: 10.1186/1755-8794-4-56
Abstract: We identified 18 publicly available gene expression datasets in the Oncomine database comparing distant metastases to primary tumors in various solid tumors which met our eligibility criteria. We performed a meta-analysis using a modified permutation counting method in order to obtain a common gene signature of metastasis. We then validated this signature in independent datasets using gene set expression comparison analysis with the LS-statistic.A common metastatic signature of 79 genes was identified in the metastatic lesions compared with primaries with a False Discovery Proportion of less than 0.1. Interestingly, all the genes in the signature, except one, were significantly down-regulated, suggesting that overcoming metastatic suppression may be a key feature common to all metastatic tumors. Pathway analysis of the significant genes showed that the genes were involved in known metastasis-associated pathways, such as integrin signaling, calcium signaling, and VEGF signaling. To validate the signature, we used an additional six expression datasets that were not used in the discovery study. Our results showed that the signature was significantly enriched in four validation sets with p-values less than 0.05.We have modified a previously published meta-analysis method and identified a common metastatic signature by comparing primary tumors versus metastases in various tumor types. This approach, as well as the gene signature identified, provides important insights to the common metastatic process and a foundation for future discoveries that could have broad application, such as drug discovery, metastasis prediction, and mechanistic studies.Metastasis, the process involving the spread of cancer, accounts for greater than 90% of cancer deaths [1]. However, therapies to treat those patients with advanced disease are largely ineffective. It is, therefore, imperative that we improve the understanding of the metastatic process and detect patients at risk for developing met
Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3
Jeffrey A. Alten, Ana Moran, Anna I. Tsimelzon, Mary-Ann A. Mastrangelo, Susan G. Hilsenbeck, Valeria Poli, David J. Tweardy
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001605
Abstract: Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3β, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients.
A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis
Robert K Dearth, Isere Kuiatse, Yu-Fen Wang, Lan Liao, Susan G Hilsenbeck, Powel H Brown, Jianming Xu, Adrian V Lee
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-377
Abstract: We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice.TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands.Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.IGF-I has the characteristics of both a circulating hormone and a tissue growth factor. While numerous studies have focused on the autocrine and/or paracrine ability of IGF-I to regulate mammary gland development and tumorigenesis [1], only a few have focused on the role of c
Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome
Jia Xu, Priya B Shetty, Weiwei Feng, Carol Chenault, Robert C Bast, Jean-Pierre J Issa, Susan G Hilsenbeck, Yinhua Yu
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-243
Abstract: Tumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival.In this study, we found that ER was associated with RASSF1A methylation (p?<?0.001) and HIN-1 methylation (p?=?0.002). PR was associated with RIL methylation (p?=?0.012), HIN-1 (p?=?0.002), and RASSF1A methylation (p?=?0.019). Tumor size was associated with RIL and CDH13 methylation (both p?=?0.002), and S-phase was associated with RIL methylation (p?=?0.036). Only RASSF1A was associated with worse time to first recurrence (p?=?0.045) and worse overall survival (p?=?0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor.Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.
β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib
Catherine Huang, Catherine C Park, Susan G Hilsenbeck, Robin Ward, Mothaffar F Rimawi, Yen-chao Wang, Jiang Shou, Mina J Bissell, C Kent Osborne, Rachel Schiff
Breast Cancer Research , 2011, DOI: 10.1186/bcr2936
Abstract: We developed a panel of HER2-overexpressing cell lines resistant to L, T, and the potent LT combination through long-term exposure and validated these models in 3D culture. Parental and L/T/LT-resistant cells were subject to HER2 and β1 integrin inhibitors in 3D and monitored for 12 days, followed by quantification of colony number. Parallel experiments were conducted where cells were either stained for Ki-67 and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or harvested for protein and analyzed by immunoblot. Results were subjected to statistical testing using analysis of variance and linear contrasts, followed by adjustment with the Sidak method.Using multiple cell lines including BT474 and HCC1954, we reveal that in L and LT resistance, where phosphorylation of EGFR/HER1, HER2, and HER3 are strongly inhibited, kinases downstream of β1 integrin--including focal adhesion kinase (FAK) and Src--are up-regulated. Blockade of β1 by the antibody AIIB2 abrogates this up-regulation and functionally achieves significant growth inhibition of L and LT resistant cells in 3D, without dramatically affecting the parental cells. SiRNA against β1 as well as pharmacologic inhibition of FAK achieve the same growth inhibitory effect. In contrast, trastuzumab-resistant cells, which retain high levels of phosphorylated EGFR/HER1, HER2, and HER3, are only modestly growth-inhibited by AIIB2.Our data suggest that HER2 activity, which is suppressed in resistance involving L but not T alone, dictates whether β1 mediates an alternative pathway driving resistance. Our findings justify clinical studies investigating the inhibition of β1 or its downstream signaling moieties as strategies to overcome acquired L and LT resistance.The HER signaling pathway is one of the most studied and prominent drivers of human breast cancer progression. Aberrant overexpression, activation, and dimerization of the individual members of the HER family--comprised of EGFR (Epidermal Growth Fa
Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression
Brandy M Heckman-Stoddard, Tracy Vargo-Gogola, Peter R McHenry, Vivian Jiang, Matthew P Herrick, Susan G Hilsenbeck, Jeffrey Settleman, Jeffrey M Rosen
Breast Cancer Research , 2009, DOI: 10.1186/bcr2352
Abstract: To investigate the effects of loss of p190B function on mammary tumor progression, p190B heterozygous mice were crossed with an MMTV-Neu breast cancer model. Effects of p190B deficiency on tumor latency, multiplicity, growth, preneoplastic progression and metastasis were evaluated. To investigate potential differences in tumor angiogenesis between the two groups, immunohistochemistry to detect von Willebrand factor was performed and quantified. To examine gene expression of potential mediators of the angiogenic switch, an angiogenesis PCR array was utilized and results were confirmed using immunohistochemistry. Finally, reciprocal transplantation of tumor fragments was performed to determine the impact of stromal deficiency of p190B on tumor angiogenesis.P190B deficiency reduced tumor penetrance (53% of p190B+/-Neu mice vs. 100% of p190B+/+Neu mice formed tumors) and markedly delayed tumor onset by an average of 46 weeks. Tumor multiplicity was also decreased, but an increase in the number of preneoplastic lesions was detected indicating that p190B deficiency inhibited preneoplastic progression. Angiogenesis was decreased in the p190B heterozygous tumors, and expression of a potent angiogenic inhibitor, thrombospondin-1, was elevated in p190B+/-Neu mammary glands. Transplantation of p190B+/-Neu tumor fragments into wild-type recipients restored tumor angiogenesis. Strikingly, p190B+/+Neu tumor fragments were unable to grow when transplanted into p190B+/-Neu recipients.These data suggest that p190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation. Furthermore, p190B deficiency in the vasculature is responsible, in part, for the inhibition of MMTV-Neu tumor progression.Small GTPases of the Rho family act as nodes of signal transduction, integrating extracellular signals to affect actin cytoskeletal organization, cell adhesion, polarity, proliferation and migration, which are all important processes that become deregulated during cancer progressi
Selective Small Molecule Stat3 Inhibitor Reduces Breast Cancer Tumor-Initiating Cells and Improves Recurrence Free Survival in a Human-Xenograft Model
Bhuvanesh Dave, Melissa D. Landis, Lacey E. Dobrolecki, Meng-Fen Wu, Xiaomei Zhang, Thomas F. Westbrook, Susan G. Hilsenbeck, Dan Liu, Michael T. Lewis, David J. Tweardy, Jenny C. Chang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030207
Abstract: Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24?/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24?/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.
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