Using ribosomal protein expression patterns as cancer biomarker

A research team at the University of Basel’s Biozentrum has investigated the expression of ribosomal proteins in a wide range of human tissues including tumors and discovered a cancer type specific signature. The study is reported in journal Genome Biology. Researchers think that these signature could be used for predicting progression and survival.

Gene expression level of individual ribosomal proteins (RP) in different types of cancer (blue: lower level; red: higher level compared to normal tissue). Credit: Mihaela Zavolan and Joao Guimaraes, University of Basel, Biozentrum

Prof. Mihaela Zavolan’s research group at the Biozentrum of the University of Basel has now discovered that about a quarter of the ribosomal proteins have tissue-specific expression and that different cancer types have their own individual expression pattern of ribosomal proteins. In the future, these patterns may serve as a prognostic marker for cancer and may point towards new therapeutic opportunities.

Mihaela Zavolan and her co-worker Joao Guimaraes have systematically analyzed ribosomal protein expression in thirty tissue types, three hundred different cell types and sixteen different types of tumors, such as lung and breast cancer. In contrast to previous assumptions, they found a wide variability in ribosomal protein gene expression. In particular, hematopoietic and tumor cells display the most complex expression pattern.

“For us, it was really impressive to see that consistent signatures emerged for the different cancer types after the analysis of distinct data sets including patient samples,” explains first author Guimaraes. “The pattern of the dysregulated proteins is very striking, whereby the expression of some ribosomal proteins is systematically reduced, and of others increased in cancer cells. This suggests that individual ribosomal proteins can either suppress or promote tumorogenesis.”

Furthermore, the scientists discovered a strong relationship between the “signature” in breast cancer and the relapse-free survival. “We were quite surprised to find that the expression level of just three ribosomal proteins allows a fairly accurate prognosis of disease progression, comparable to the best predictive markers that are currently known”, Zavolan points out.

“Our study demonstrates the potential of such expression signatures for the prognosis and perhaps a diagnosis of cancer. We are especially interested in studying the functions of individual ribosomal proteins and hopefully opening the door for new therapeutic options,” explains the scientist.
Citation: Guimaraes, Joao C., and Mihaela Zavolan. “Patterns of ribosomal protein expression specify normal and malignant human cells.” Genome Biology 2016 17:236.
DOI: 10.1186/s13059-016-1104-z
Adapted from press release by University of Basel.

Piperlongumine, chemical from Indian pepper plant inhibits enzyme in cancer cells

UT Southwestern Medical Center scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The study is published in the Journal of Biological Chemistry.

Dr. Westover’s lab used X-ray crystallography to create this molecular model of piperlongumine.
Credit: UT Southwestern

The secret lies in a chemical called Piperlongumine (PL), which has shown activity against many cancers including prostate, breast, lung, colon, lymphoma, leukemia, primary brain tumors, and gastric cancer.

Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. Piperlongumine (PL) converts to hPiperlongumine (hPL), an active drug that silences a gene called GSTP1. The GSTP1 gene produces a detoxification enzyme Glutathione S-Transferase Pi 1 that is often overly abundant in tumors.

“We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies,” said Dr. Kenneth Westover, Assistant Professor of Biochemistry and Radiation Oncology. “This research is a spectacular demonstration of the power of x-ray crystallography.”

Dr. Westover, a member of the Harold C. Simmons Comprehensive Cancer Center, used cutting edge technologies in UT Southwestern’s Structural Biology Core (SBC) – the University’s world-renowned facility for X-ray crystallography, to better understand the anticancer properties of Piperlongumine (PL). X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets – in this case how Piperlongumine (PL) interacts with GSTP1. Viewing the structures helps in developing drugs for those targets.

Citation: Harshbarger, Wayne, Sudershan Gondi, Scott B. Ficarro, John Hunter, Durga Udayakumar, Deepak Gurbani, William Singer, Yan Liu, Lianbo Li, Jarrod A. Marto and Kenneth D. Westover. “Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.” Journal of Biological Chemistry (2016): jbc-M116.
DOI: 10.1074/jbc.M116.750299
Research funding: V Foundation for Cancer Research, Welch Foundation, and Cancer Prevention and Research Institute of Texas.
Adapted from press release by UT Southwestern Medical Center.

Capsaicin, an active ingredient of chili peppers found to inhibit breast cancer cells in vitro

Capsaicin, an active ingredient of pungent substances such as chili or pepper, inhibits the growth of breast cancer cells. This was reported by a team headed by the Bochum-based scent researcher  Prof. Dr. Dr. Dr. med. habil. Hanns Hatt and Dr. Lea Weber, following experiments in cultivated tumor cells. The study was published in the journal “Breast Cancer – Targets and Therapy”.

The experiments were carried out with the SUM149PT cell culture, a model system for a particularly aggressive type of breast cancer, i.e. the triple-negative type. Chemotherapy is currently the only available treatment for this type of cancer.

In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional – a scent of fresh sea breeze.

In collaboration with Dr. Gabriele Bonatz from the Augusta clinics in Bochum (Brustzentrum), Hatt’s team confirmed the existence of TRPV1 in tumor cells in nine different samples from patients suffering from breast cancer.

The researchers activated the TRPV1 receptor in the cell culture with capsaicin or helional, by adding the substances to the culture for a period of several hours or days. As a result, the cancer cells divided more slowly. Moreover, the treatment caused tumour cells to die in larger numbers. The surviving cells were no longer able to move as quickly as heretofore; this implies that their ability to form metastases in the body was impeded.

“If we could switch on the TRPV1 receptor with specific drugs, this might constitute a new treatment approach for this type of cancer,” says Hanns Hatt. An intake via food or inhalation is insufficient for this purpose.

Earlier studies had demonstrated that the chemical arvanil – with a chemical make-up similar to that of the spicy molecule capsaicin – was effective against brain tumours in mice; it reduces tumour growth in the animals. Due to its side effects, however, this substance is not approved for humans. In addition to capsaicin and helional, the endovanilloids, produced naturally in the body, also activate the TRPV1 receptor.

Citation: Weber, Lea V, Klaudia Al-Refae, Gerhard Wölk, Gabriele Bonatz, Janine Altmüller, Christian Becker, Günter Gisselmann & Hanns Hatt. “Expression and functionality of TRPV1 in breast cancer cells”. Breast Cancer: Targets and Therapy 2016 vol: Volume 8 pp: 243-252.
DOI: 10.2147/BCTT.S121610
Research funding:  Heinrich-und-Alma-Vogelsang-Stiftung, German Research Foundation.
Adapted from press release by Ruhr-Universitaet-Bochum.

New approach to targeted cancer treatment and imaging by utilizing glycosidase activation of glyconaphthalimides.

Scientists from Trinity College Dublin have uncovered a new class of compounds glyconaphthalimides that can be used to target cancer cells with greater specificity than current options allow. The study was published in the journal Chemical Communications.

Cervical cancer cells show green fluorescence from enzyme-activated compound.
Credit: Eoin Scanlan, Trinity College Dublin.

Cancer is difficult to treat, and many current therapies are unable to specifically target cancer cells. This is problematic for medical professionals and patients, because it limits the dose of the drug that can be safely administered, and often causes severe and debilitating side-effects.

But the Trinity scientists have now demonstrated that a class of naturally occurring enzymes  glycosidases  that are heavily overexpressed in tumor tissue can be used to trigger the release of therapeutic payloads only in the local tumor sites where they are needed.

This finding may therefore result in the development of improved targeted cancer therapies with significantly reduced side-effects for patients.

In addition to killing cancer cells, the technology may also be used to image cancer cells, with potential applications in cancer imaging and diagnosis.

Associate Professor in Chemistry at Trinity, Eoin Scanlan, led the multidisciplinary group. He said: “This is a really exciting discovery because it brings us closer to more targeted treatment of cancer. Some current therapies are limited due to the toxicity of the compounds, but our compounds are completely inactive until they are released by the enzymes that are naturally overexpressed at the tumour site. The active compound is then rapidly taken up by cancer cells.”

“Our next steps will be to apply this technology to release specific anti-cancer drugs and to test it against a range of different cancer types.”

Citation: Calatrava-Pérez, Elena, Sandra A. Bright, Stefan Achermann, Claire Moylan, Mathias O. Senge, Emma B. Veale, D. Clive Williams, Thorfinnur Gunnlaugsson, and Eoin M. Scanlan. “Glycosidase activated release of fluorescent 1, 8-naphthalimide probes for tumor cell imaging from glycosylated ‘pro-probes’.” Chemical Communications 52, no. 89 (2016): 13086-13089.
DOI: 10.1039/C6CC06451E 
Research funding: Science Foundation Ireland.
Adapted from press release by Trinity College Dublin.

New lung cancer biomarker Protein PD-1 for predicting survival

The biomarker PD-1, a protein, could potentially be used to predict survival or disease-free survival of lung cancer patients who have had the tumor surgically removed. This is substantiated by the results of a study conducted under the direction of the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital, together with MedUni Graz and the University of Novi Sad. The paper was presented at the 17th World Conference on Lung Cancer (Dec 2016)

PD-1 protein expression predicts survival in resected adenocarcinomas of the lung. Credit: Medical university of Vienna

In Austria, around 4,000 people develop lung cancer every year. Around three-quarters of these cases involve so-called Non-Small Cell Lung Cancer (or NSCLC). In turn, half of these, that is to say around 1,400 people, are diagnosed as having adenocarcinomas, the commonest subtype of NSCLC. The earlier the disease is detected, the better the patient’s chances of recovery. Essentially, the options for treatment are surgery, radiotherapy, chemotherapy (before and after surgery), a combination of these methods and, very recently, immunotherapy.

Scientists led by Martin Filipits, a cancer researcher at MedUni Vienna’s Institute of Cancer Research and member of CCC Vienna, has now been able to show that PD-1, a protein that occurs on the surface of the body’s immune cells, could serve as a biomarker for predicting the survival of patients with adenocarcinomas. PD-1 is a so-called immune checkpoint protein. Immune checkpoints monitor the correct functioning of the immune response and check an ongoing immune reaction. That is important, as otherwise the immune response could overshoot and give rise to autoimmune diseases.

In the study, the researchers examined cancer cells and immune system cells from 159 patients. All of these patients had previously had cancer resected and some of them had received chemotherapy afterward. PD-1 was found on the immune cells of 45% of the patients and PD-L1 on the cancer cells in 37% of them. The investigation clearly showed that both survival and disease-free survival was longer in the patients in which PD-1 was found than in those where it was not. On the other hand, it made no difference to the prognosis whether PD-L1 was present on the cancer cells or not.

Filipits: “Our results indicate that PD-1 could serve as a biomarker for predicting the survival of patients with an operable adenocarcinoma of the lung. This finding still needs to be confirmed in further studies but it indicates the direction for further research.”

Citation: Zaric, Bojan, Luka Brcic, Anna Buder, Christian Tomuta, Anita Brandstetter, Jorun O. Buresch, Stefan Traint, Vladimir Stojsic, Tomi Kovacevic, Branislav Perin, Robert Pirker and Martin Filipits. “PD-1 protein expression predicts survival in resected adenocarcinomas of the lung.” 17th World Conference on Lung Cancer, Vienna, Dec 2016.
Adapted from press release by the Medical University of Vienna.

Research shows possible link between "body clock" and cancer pathogenesis

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily “circadian” clocks in influencing cancer growth. The research, published in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked.

“This appears to have big implications for the connection between circadian rhythms and cancer,” said TSRI biologist Katja Lamia, senior author of the study.

There is growing evidence that shift work and frequent jet lag can raise a person’s risk of cancer, suggesting a link between daily rhythms and cell growth. “We know this connection exists, but we haven’t known why,” said Lamia.

The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more.

Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells’ ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation similar to the abnormal growth seen in cancers.

Further studies of protein structures suggested that CRY2 is a key player in a process to “mark” cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription once the proteins are already produced rather than during transcription, as in many other cryptochrome functions.

“This is a function of a circadian protein that has never been seen before,” said TSRI Research Associate Anne-Laure Huber, who served as first author of the study.

The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.

Citation: “CRY2 and FBXL3 Cooperatively Degrade c-MYC”. Anne-Laure Huber, Stephanie J. Papp, Alanna B. Chan, Emma Henriksson, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M. Metallo, Katja A. Lamia. Molecular Cell 2016 vol: 64 (4) pp: 774-789.
DOI: 10.1016/j.molcel.2016.10.012
Research funding: National Institutes of Health, Searle Scholars Program through the Kinship Foundation, Sidney Kimmel Foundation, Lung Cancer Research Foundation, Swedish Research Council, Deutsche Forschungsgemeinschaft and American Heart Association.
Adapted from press release by The Scripps Research Institute.

Research shows possible link between “body clock” and cancer pathogenesis

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily “circadian” clocks in influencing cancer growth. The research, published in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked.

“This appears to have big implications for the connection between circadian rhythms and cancer,” said TSRI biologist Katja Lamia, senior author of the study.

There is growing evidence that shift work and frequent jet lag can raise a person’s risk of cancer, suggesting a link between daily rhythms and cell growth. “We know this connection exists, but we haven’t known why,” said Lamia.

The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more.

Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells’ ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation similar to the abnormal growth seen in cancers.

Further studies of protein structures suggested that CRY2 is a key player in a process to “mark” cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription once the proteins are already produced rather than during transcription, as in many other cryptochrome functions.

“This is a function of a circadian protein that has never been seen before,” said TSRI Research Associate Anne-Laure Huber, who served as first author of the study.

The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.

Citation: “CRY2 and FBXL3 Cooperatively Degrade c-MYC”. Anne-Laure Huber, Stephanie J. Papp, Alanna B. Chan, Emma Henriksson, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M. Metallo, Katja A. Lamia. Molecular Cell 2016 vol: 64 (4) pp: 774-789.
DOI: 10.1016/j.molcel.2016.10.012
Research funding: National Institutes of Health, Searle Scholars Program through the Kinship Foundation, Sidney Kimmel Foundation, Lung Cancer Research Foundation, Swedish Research Council, Deutsche Forschungsgemeinschaft and American Heart Association.
Adapted from press release by The Scripps Research Institute.

Lab study shows how metformin can protect against cancer

Researchers at University of California San Diego School of Medicine have identified a previously unknown mechanism that helps fortify the structure and tight junctions between epithelial cells, a basic cell type that lines various body cavities and organs throughout the body, forming a protective barrier against toxins, pathogens, and inflammatory triggers. Breaches of this barrier can provoke organ dysfunction and development of tumors.

The findings, published online in the current issue of eLife by senior author Pradipta Ghosh, MD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues, helps illuminate why the widely prescribed anti-diabetic drug Metformin has repeatedly been shown to not only protect epithelial integrity in the face of stressors like inflammation, sepsis, hypoxia and harmful microbes but also appears to prevent cancer.

Virtually all cell types possess cell polarity, the asymmetrical organization of their components and structures that makes it possible for them to carry out specialized functions. In epithelial cells, polarity determines how they form barriers. Loss of epithelial polarity impacts organ development and function and can initiate cancers.

The stress-polarity pathway, discovered and described in 2006 and 2007, is a specialized pathway mobilized only during periods of stress. It is orchestrated by a protein-kinase called AMPK that protects cellular polarity when epithelial cells are under energetic stress and an activator of AMPK called LBK1.

“The latter is a bona fide tumor suppressor,” said Ghosh. Mutations in LBK1 have been linked to cancers and loss of cell polarity. While the question of exactly how the energy-sensing LKB1-AMPK pathway maintains cell polarity during stress remained unknown for more than a decade, evidence accumulated that Metformin, an activator of the LKB1-AMPK pathway and a frontline treatment for type 2 diabetes, has beneficial effects on the epithelial lining and can potentially prevent cancer.

The new research, said Ghosh, provides “mechanistic insights into the tumor-suppressive action of Metformin and the LKB1-AMPK pathway at a higher resolution.” Specifically, she and colleagues discovered that the stress-polarity pathway requires a key effector of AMPK, a protein called GIV/Girdin.

In cultured polarized epithelial cells, the authors demonstrated that AMPK and its activator Metformin exerted much of their beneficial effects via phosphorylating GIV and directing GIV to the tight junctions of the epithelial layer. Without such phosphorylation and/or targeting, the beneficial effects of AMPK, and its activator Metformin were virtually abolished and the epithelial barrier became “leaky” and eventually collapsed. Mutants of GIV found in colon cancer that specifically abolishes AMPK’s ability to phosphorylate GIV could trigger tumor cell growth in 3D matrigel.

Research authors feel that this study provided new insights into the epithelium-protecting and tumor-suppressive actions of one of the most widely prescribed drugs, Metformin, which may inspire a fresh look and better-designed studies to fully evaluate the benefits of this relatively cheap medication.

Citation: Aznar, Nicolas, Arjun Patel, Cristina C. Rohena, Ying Dunkel, Linda P. Joosen, Vanessa Taupin, Irina Kufareva, Marilyn G. Farquhar, and Pradipta Ghosh. “AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.” eLife 5 (2016): e20795.
DOI: http://dx.doi.org/10.7554/eLife.20795
Research funding: National Institutes of Health, Burroughs Wellcome Fund, American Cancer Society, UC San Diego Moores Cancer Center.
Adapted from press release by University of California – San Diego

Protein CPEB4 plays crucial role in melanoma

Spanish National Cancer Research Centre (CNIO) Melanoma Group researchers work tirelessly to identify biomarkers of tumor progression and to validate novel therapeutic targets in melanoma. In particular, their research focuses on discovering features that define the “fingerprint” of this tumor, features that distinguish it from other cancer types. The latest study in this area, published in Nature Communications, describes the roles of CPEB4; a protein that is crucial for melanoma cell survival. The group headed by Marisol Soengas, senior author of this paper, is an expert in researching the “identity” of melanomas.

High levels of CPEB4 expression in human melanoma. The image shows a melanoma
biopsy stained for CPEB4 factor (in red) and one of its target genes (RAB27, in green).
Credit: Centro Nacional de Investigaciones Oncológicas (CNIO)

“In previous studies, we have demonstrated that melanomas are very different from other types of tumors in that they activate mechanisms of self-degradation (autophagy), or control the internalization and secretion of molecules, for example,” explains Soengas. They have now found that the CPEB4 protein, which is of great interest in the cancer field, plays a selective and essential role in melanoma cells.

In broad terms, CPEBs are involved in the regulation of gene expression and are associated with important cellular processes, such as cell division, cell differentiation, or cell polarity and migration. In tumors, the expression of CPEBs varies, and seemingly opposing, pro- and antitumor, roles have been described in other tumor types but not in melanoma.

CPEB4, a member of this family, was “especially attractive” to the authors “given its overexpression in tumors such as gliomas and pancreatic carcinomas, which are also aggressive”. As they noted, the levels of this protein were very high in melanoma from the early stages of the disease, which made the researchers suspect its association with cell proliferation. What they did not know was the extent of it.

Soengas’ group compared the effects of CEPB4 on various tumors, and noted that melanoma cells were “more dependent on this protein”, since its inhibition greatly hindered the proliferation of these cells. This ‘addiction’ makes melanoma more vulnerable to drugs targeting this pathway, and can be a novel target for therapeutic intervention in melanoma.

The researchers also describe that melanomas depend so tightly on CPEB4 because this protein regulates the expression of factors such as MITF and RAB27A, which have unique functions in this tumor type. CPEB4, is therefore a main driver of the “intrinsic signature” that separates melanomas from other pathologies, concludes Soengas.

Citation: “Lineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers”. Eva Pérez-Guijarro, Panagiotis Karras, Metehan Cifdaloz, Raúl Martínez-Herranz, Estela Cañón, Osvaldo Graña, Celia Horcajada-Reales, Direna Alonso-Curbelo, Tonantzin G. Calvo, Gonzalo Gómez-López, Nicolas Bellora, Erica Riveiro-Falkenbach, Pablo L. Ortiz-Romero, José L. Rodríguez-Peralto, Lorena Maestre, Giovanna Roncador, Juan C. de Agustín Asensio, Colin R. Goding, Eduardo Eyras, Diego Megías, Raúl Méndez & María S. Soengas.
Nature Communications, 2016 vol: 7 pp: 13418.
DOI: http://dx.doi.org/10.1038/ncomms13418
Research funding: Marató TVE, Spanish Ministry of Economy and Competitiveness, Fundación Botín, Banco Santander, Spanish Ministry of Health, Fundación Sandra Ibarra, Ludwig Institute for Cancer Research
Adapted from press release by Centro Nacional de Investigaciones Oncológicas (CNIO)

Over expression of protein BRD4 associated with breast cancer metastasis

Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread. The findings, which appear in the journal Cancer Research, may provide a new target to suppress breast cancer metastasis.

Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.

Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumors and found that tumors with a high expression of BRD4 were more likely to metastasize.

“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.

Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.

Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.

Citation: Andrieu, Guillaume, Anna H. Tran, Katherine J. Strissel, and Gerald V. Denis. “BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling.” Cancer Research (2016): canres-0559.
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-16-0559
Research funding: NIH/National Cancer Institute
Adapted from press release by Boston Univsersity School of Medicine