Department of Pathology, Anatomy and Cell Biology Faculty Papers

The Dermatan Sulfate Proteoglycan Decorin Modulates α2β1 Integrin and the Vimentin Intermediate Filament System during Collagen Synthesis.

Oliver Jungmann et al. — Thu, 03 Jan 2013 08:24:05 PST

Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn(-/-)) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn(-/-) mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn(-/-) fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of decorin. We discovered that a decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn(-/-) fibroblasts. This phenotype could be rescued by the decorin proteoglycan but less efficiently by the decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn(-/-) fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn(-/-). Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn(-/-) phenotype.

Knockdown of ki-67 by dicer-substrate small interfering RNA sensitizes bladder cancer cells to curcumin-induced tumor inhibition.

Sivakamasundari Pichu et al. — Wed, 19 Dec 2012 13:41:01 PST

Transitional cell carcinoma (TCC) of the urinary bladder is the most common cancer of the urinary tract. Most of the TCC cases are of the superficial type and are treated with transurethral resection (TUR). However, the recurrence rate is high and the current treatments have the drawback of inducing strong systemic toxicity or cause painful cystitis. Therefore, it would be of therapeutic value to develop novel concepts and identify novel drugs for the treatment of bladder cancer. Ki-67 is a large nucleolar phosphoprotein whose expression is tightly linked to cell proliferation, and curcumin, a phytochemical derived from the rhizome Curcuma longa, has been shown to possess powerful anticancer properties. In this study, we evaluated the combined efficacy of curcumin and a siRNA against Ki-67 mRNA (Ki-67-7) in rat (AY-27) and human (T-24) bladder cancer cells. The anticancer effects were assessed by the determination of cell viability, apoptosis and cell cycle analysis. Ki-67-7 (10 nM) and curcumin (10 µM), when treated independently, were moderately effective. However, in their combined presence, proliferation of bladder cancer cells was profoundly (>85%) inhibited; the rate of apoptosis in the combined presence of curcumin and Ki-67-7 (36%) was greater than that due to Ki-67-7 (14%) or curcumin (13%) alone. A similar synergy between curcumin and Ki-67-7 in inducing cell cycle arrest was also observed. Western blot analysis suggested that pretreatment with Ki-67-7 sensitized bladder cancer cells to curcumin-mediated apoptosis and cell cycle arrest by p53- and p21-independent mechanisms. These data suggest that a combination of anti-Ki-67 siRNA and curcumin could be a viable treatment against the proliferation of bladder cancer cells.

COP9 signalosome component JAB1/CSN5 is necessary for T cell signaling through LFA-1 and HIV-1 replication.

Shigemi M Kinoshita et al. — Wed, 19 Dec 2012 12:31:17 PST

To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4(+) T cells. This peptide blocked physiological release of JAB1 from the accessory T cell surface protein LFA-1, downstream AP-1 dependent events, NFAT activation, and HIV-1 replication. Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.

Lung carcinoma in the era of personalized medicine: the role of cytology.

Maureen F Zakowski et al. — Wed, 19 Dec 2012 11:03:25 PST

In 2004, three groups working independently [1–3] , almost simultaneously, reported remarkable findings: that activating mutations in the epidermal growth factor receptor (EGFR) were common in certain lung carcinomas and that these mutations correlated with the response of those lung tumors to therapy with gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs). This was the first time driver mutations in lung cancer that responded to targeted therapy had been identified, marking the beginning of a new era of personalized medicine in lung cancer. Prior to the discovery of these mutations, patients had been treated with EGFR TKIs but predicting who would respond and who would not was only imperfectly correlated with the histologic appearance of the tumor and the clinical profile of the patient.

Decorin antagonizes the angiogenic network: Concurrent inhibition of met, hypoxia inducible factor 1α, vascular endothelial growth factor A, and induction of thrombospondin-1 and tiMP3

Thomas Neill et al. — Mon, 24 Sep 2012 13:19:37 PDT

Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Mini-Review: Decorin, a Guardian from the Matrix

Thomas Neill et al. — Mon, 24 Sep 2012 12:27:35 PDT

Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor-β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of growth factors or directly via the antagonism of receptor tyrosine kinases. We propose that decorin can be considered a "guardian from the matrix" because of its innate ability to oppose pro-tumorigenic cues.

Thomas Jefferson University, Department of Pathology, Anatomy and Cell Biology, Oral Administration of Apigenin Inhibits Metastasis through AKT/P70S6K1/MMP-9 Pathway in Orthotopic Ovarian Tumor Model.

Jun He et al. — Fri, 03 Aug 2012 12:55:31 PDT

Apigenin, a flavonoid commonly present in the daily diet, is known for its potential anti-tumor properties. However, the effect of apigenin via oral administration on tumor growth and metastasis remains unknown. In this study we developed an orthotopic ovarian tumor model in nude mice to test the effect of apigenin oral administration, and showed that apigenin inhibited the micrometastasis of cancer cells in the animal tumor model. To understand the mechanism of apigenin in inhibiting metastasis, we found that apigenin greatly inhibited MMP-9 expression and p-AKT and p-p70S6K1 levels in the tumor tissues compared to the control group. We further demonstrated that the downregulation of MMP-9 by apigenin was mediated by the AKT/p70S6K1 pathway. These findings help to address the question with common interests to the public of whether oral uptake of flavonoids is effective in preventing cancer. Our results demonstrate for the first time that oral uptake of apigenin can inhibit tumor metastasis through MMP-9 expression using the orthotopic ovarian tumor model.

Integrative gene regulatory network analysis reveals light-induced regional gene expression phase shift programs in the mouse suprachiasmatic nucleus.

Haisun Zhu et al. — Fri, 03 Aug 2012 09:47:06 PDT

We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a "functional gene expression program", e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further understand this multigenic program. By use of high-throughput qPCR we studied 52 small samples taken by anatomically precise laser capture from within the core and shell SCN regions, and taken at time points with and without phase resetting light exposure. The results show striking regional differences in light response to be present in the mouse SCN. By using network-based analyses, we are able to establish a highly specific multigenic correlation between genes expressed in response to light at night and genes normally activated during the day. The light pulse triggers a complex and highly coordinated network of gene regulation. The largest differences marking neuroanatomical location are in transmitter receptors, and the largest time-dependent differences occur in clock-related genes. Nighttime phase resetting appears to recruit transcriptional regulatory processes normally active in the day. This program, or mechanism, causes the pattern of core region gene expression to transiently shift to become more like that of the shell region.

Decorin-mediated inhibition of colorectal cancer growth and migration is associated with E-cadherin in vitro and in mice.

Xiuli Bi et al. — Tue, 24 Jul 2012 13:01:35 PDT

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin in human colorectal cancer cells, we found that E-cadherin, a protein that regulates cell-cell adhesion, epithelial-mesenchymal transition and metastasis, was almost completely lost in Dcn(-/-) mouse intestine, and loss of decorin and E-cadherin accelerated colon cancer cell growth and invasion in Dcn(-/-) mice. However, increasing decorin expression in colorectal cancer cells attenuated cancer cell malignancy, including inhibition of cancer cell proliferation, promotion of apoptosis and importantly, attenuation of cancer cell migration. All these changes were linked to the regulation of E-cadherin by decorin. Moreover, overexpression of decorin upregulated E-cadherin through increasing of E-cadherin protein stability as E-cadherin messenger RNA and promoter activity were not affected. Co-immunoprecipitation assay showed a physical binding between decorin and E-cadherin proteins. Taken together, our results provide direct evidence that decorin-mediated inhibition of colorectal cancer growth and migration are through the interaction with and stabilization of E-cadherin.

Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells

Marco Genua et al. — Tue, 24 Jul 2012 12:53:42 PDT

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer. © 2012 Genua et al.

Graft Versus Host Disease of the Brain Following Allogeneic Stem Cell Transplant for Myelodysplastic Syndrome

Janet Yoo et al. — Mon, 02 Jul 2012 11:16:06 PDT

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality following bone marrow transplantation (BMT). GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. GVHD, which can present either acutely or chronically, typically involves the skin, gastrointestinal tract, and liver. In contrast, GVHD involving other organs such as the heart and kidney is highly uncommon and involvement of the central nervous system has only very rarely been described in the literature. We report an unusual case of GVHD that involved the heart, kidney, adrenals, and the brain in a deceased patient that received a dual haploidentical stem cell transplant for myelodysplastic syndrome. Pre-mortem, the patient had experienced biopsy proven GVHD of the skin and liver. The clinical course was also complicated by fungal infection (Rhizopus). There was no histologic evidence of viral infection pre or post-mortem. Pre-mortem PCR analysis of nasopharyngeal swabs was negative for respiratory viruses. PCR also failed to identify BK virus or CMV from blood or urine. GVHD of the CNS was characterized by a lymphocytic leptomeningitis with few perivascular multinucleated giant cells. Immunohistochemical studies demonstrated both CD8+ and CD4+ lymphocytes in the leptomeninges and the brain parenchyma with a marked predominance of CD8+ lymphocytes. CD20 and VZV immunohistochemistry was negative. Post-mortem PCR analysis of short tandem repeat (STR) polymorphisms demonstrated a range of ~20-50% of both donors’ cells in multiple organs, likely lymphocytes, based on the H&E examination. However, due to prolonged formalin fixation, no PCR signal could be detected in the brain. GVHD of the CNS is rare but may be underreported due to the declining autopsy rate and a lack of recognition of the salient histologic features.

A View from the Outside: Iron going to tell you a story HIF you'll listen and other horrible puns

Richard A. Brigandi, MD, PhD, FAAP — Thu, 10 May 2012 12:02:36 PDT

Presentation was given as part of the Jefferson College of Graduate Studies Alumni Day activities. Dr. Brigandi was recipient of the Distinguished Alumni Award for 2012.

Presentation length: 1 hour and 20 minutes.

The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma.

Jean-Marc Navenot et al. — Fri, 27 Apr 2012 08:05:05 PDT

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS prompted us to revisit the C8161.9 model. We found that the cells expressing KISS1, used in the previous study and obtained by transfection and single-cell cloning, were defective for both formation of orthotopic tumors and metastases. In mixing experiments, these cells could not suppress orthotopic tumor growth of KISS1-negative C8161.9 cells, suggesting that the suppression of metastasis by C8161.9-KISS1 cells may be intrinsic to the selected clone rather than related to KISS1 expression. Isolation of clones from parental C8161.9 cells in soft agar yielded cell populations that phenotypically and genotypically mimicked the KISS1-positive clone. In addition, new clones expressing KISS1 did not show any decrease in metastatic growth. These data demonstrate the heterogeneity of cell types in the C8161.9 cell line and the high risk of artifact linked to single-cell selection. A different xenograft model will be necessary to evaluate the use of KISS1 analogs as antimetastatic therapy.

N-glycosylation status of E-cadherin controls cytoskeletal dynamics through the organization of distinct β-catenin- and γ-catenin-containing AJs.

Basem T Jamal et al. — Thu, 19 Apr 2012 09:43:21 PDT

N-glycosylation of E-cadherin has been shown to inhibit cell-cell adhesion. Specifically, our recent studies have provided evidence that the reduction of E-cadherin N-glycosylation promoted the recruitment of stabilizing components, vinculin and serine/threonine protein phosphatase 2A (PP2A), to adherens junctions (AJs) and enhanced the association of AJs with the actin cytoskeleton. Here, we examined the details of how N-glycosylation of E-cadherin affected the molecular organization of AJs and their cytoskeletal interactions. Using the hypoglycosylated E-cadherin variant, V13, we show that V13/β-catenin complexes preferentially interacted with PP2A and with the microtubule motor protein dynein. This correlated with dephosphorylation of the microtubule-associated protein tau, suggesting that increased association of PP2A with V13-containing AJs promoted their tethering to microtubules. On the other hand V13/γ-catenin complexes associated more with vinculin, suggesting that they mediated the interaction of AJs with the actin cytoskeleton. N-glycosylation driven changes in the molecular organization of AJs were physiologically significant because transfection of V13 into A253 cancer cells, lacking both mature AJs and tight junctions (TJs), promoted the formation of stable AJs and enhanced the function of TJs to a greater extent than wild-type E-cadherin. These studies provide the first mechanistic insights into how N-glycosylation of E-cadherin drives changes in AJ composition through the assembly of distinct β-catenin- and γ-catenin-containing scaffolds that impact the interaction with different cytoskeletal components.

Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice.

Hongxia Zhou et al. — Tue, 17 Apr 2012 13:24:03 PDT

Transgenic RNAi, an alternative to the gene knockout approach, can induce hypomorphic phenotypes that resemble those of the gene knockout in mice. Conditional transgenic RNAi is an attractive choice of method for reverse genetics in vivo because it can achieve temporal and spatial silencing of targeted genes. Pol III promoters such as U6 are widely used to drive the expression of RNAi transgenes in animals. Tested in transgenic mice, a Cre-loxP inducible U6 promoter drove the broad expression of an shRNA against the Pink1 gene whose loss-of-functional mutations cause one form of familial Parkinson's disease. The expression of the shRNA was tightly regulated and, when induced, silenced the Pink1 gene product by more than 95% in mouse brain. However, these mice did not develop dopaminergic neurodegeneration, suggesting that silencing of the Pink1 gene expression from embryo in mice is insufficient to cause similar biochemical or morphological changes that are observed in Parkinson's disease. The results demonstrate that silencing of the PINK1 gene does not induce a reliable mouse model for Parkinson's disease, but that technically the inducible U6 promoter is useful for conditional RNAi in vivo.

Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications.

Jean-Pierre Louboutin et al. — Tue, 10 Apr 2012 13:16:27 PDT

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.

Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing.

Katherine E Varley et al. — Tue, 10 Apr 2012 13:16:25 PDT

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, deep into each tumor, revealed unexpectedly heterogeneous patterns of methylation at the MLH1 promoter within a subset of endometrial tumors. This high-resolution analysis allowed us to measure the clonality of methylation in individual tumors and gain insight into the accumulation of aberrant promoter methylation on both alleles during tumorigenesis.

P16/Rb Correlations in Oropharyngeal Squamous Cell Carcinoma (OSCC)

Madalina Tuluc et al. — Mon, 02 Apr 2012 12:36:08 PDT

The objective of this study is to explore the patterns of Rb expression in p16 positive and negative OSCC, in relation to patient's smoking history.

P53 Expression in Oropharyngeal Squamous Cell Carcinoma in Increased in HPV Positive Smokers

Madalina Tuluc et al. — Mon, 02 Apr 2012 12:32:28 PDT

Background and Objectives

High risk HPV is associated with oropharyngeal SCC (OSCC) and is responsible for the increasing incidence of this cancer type among younger patients.

Patients with HPV positive oropharyngeal SCC have a better prognosis when compared with HPV negative, tobacco induced SCC.

HPV E6 inactivates p53 leading to low expression of p53; tobacco induced oropharyngeal SCC is characterized by p53 overexpression, resistance to treatment and poor prognosis. However, in many cases of HPV OSCC, there is a history of current or remote smoking, making this disease a multifactorial process. We expect that smoking will influence the level of p53 expression in HPV positive smokers.

The objective of our study is to evaluate the differences in p53 expression in HPV positive and HPV negative patients, smokers and nonsmokers.

Loss of Retinoblastoma (RB) Tumor Suppressor Expression in Breast Cancer Correlates with Better Response to Neoadjuvant Chemotherapy

Jeanne McFalls, MD et al. — Mon, 02 Apr 2012 12:14:06 PDT

Conclusions:

Loss of RB tumor suppressor staining in pre-treatment breast cancer biopsies can be used prior to initiation of neoadjuvant chemotherapy to predict good tumor response. This association between RB loss and good neoadjuvant response holds regardless of ER status and across various chemotherapy regimens. Assessment of RB status in the pre-treatment biopsy could be useful clinical tool to define patients who are most likely to benefit from neoadjuvant chemotherapy.