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Obesity may increase risk of triple-negative breast cancer

New findings published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, confirm the risk of breast cancer among women who are obese and not physically active, and suggests additional mechanisms beyond estrogen.

Scientists from the Women’s Health Initiative have found a relationship between obesity, physical activity and triple-negative breast cancer, a subtype of breast cancer characterized by a lack of estrogen, progesterone and HER2 expression. Triple-negative breast cancers account for about 10 to 20 percent of all breast cancers and are associated with an extremely poor prognosis due to a lack of targeted drug therapies.

“Breast cancer is not just one disease. It is a complex combination of many diseases,” said Amanda Phipps, Ph.D., a postdoctoral fellow at the Fred Hutchinson Cancer Research Center. “The fact that we found an association with triple-negative breast cancer is unique because, biologically, this subtype is very different from other breast cancers.”

Epidemiologists have long noted a link between obesity and increased risk of postmenopausal breast cancer, as well as a decreased risk that comes with greater physical activity. A relationship between adipose tissue and estrogen is thought to contribute to this risk.

Phipps and colleagues analyzed data from the 155,723 women enrolled in the Women’s Health Initiative. They assessed levels of baseline body mass index (BMI) and recreational physical activity among the 307 women who had triple-negative breast cancer and the 2,610 women who had estrogen receptor-positive breast cancer.

Results showed that women with the highest BMI had a 35 percent increased risk of triple-negative breast cancers and a 39 percent increased risk of estrogen receptor-positive breast cancers. Those who reported high rates of physical activity had a 23 percent decreased risk of triple-negative breast cancer and a 15 percent decreased risk of estrogen receptor-positive breast cancer.

Amy Trentham-Dietz, Ph.D., an associate professor of population health sciences at the University of Wisconsin and an editorial board member of Cancer Epidemiology, Biomarkers & Prevention, said the study raises important questions.

“The body of literature, primarily meta-analyses, has shown most of the risk between obesity and breast cancer to be among the estrogen receptor-positive subtypes,” she said. “This paper raises questions about the possible role of growth factors or inflammation, but these will need to be explored with larger patient groups with known breast cancer subtypes, especially triple-negative breast cancers.”

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards. The AACR Annual Meeting attracts more than 18,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. Including Cancer Discovery, the AACR publishes seven major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. AACR journals represented 20 percent of the market share of total citations in 2009. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists.

A small subset of normal white blood cells gives rise to a rare leukemia, study shows

COLUMBUS, Ohio ? New research has identified a small subset of normal white blood cells in the body that gives rise to a rare incurable form of leukemia.

The study, led by investigators at The Ohio State University Comprehensive Cancer Center ? Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC ? James), shows that large granular lymphocyte leukemia can occur in a small subset of white blood cells called NKT cells. NKT cells share features of immune cells called T lymphocytes and features of immune cells called natural killer (NK) cells.

The discovery, published online in the Journal of Clinical Investigation, arose from studies investigating why a mouse strain engineered to overexpress interleukin-15 often develops large granular lymphocyte leukemia, a disease more common in Asia than the United States, and it points to new ways to prevent the malignancy.

The researchers show that, in mice and in humans, the novel subset of NKT cells responsible for large granular lymphocyte leukemia are marked on their surface by a protein called NKp46. Only small numbers of these cells are present in mice and in humans. The study further shows that overexpression of interleukin-15 can drive these cells but not others to become leukemic.

“These novel NKT cells represent a small white-blood-cell population in normal mice or healthy humans, but they have the potential to develop into large granular lymphocyte leukemia under certain circumstances, such as a high interleukin-15 environment,” says first author Jianhua Yu, a research scientist with the OSUCCC ? James.

“Our work suggests that targeting interleukin-15 signaling and NKp46 might offer a new way to prevent this leukemia as we learn more about who is susceptible,” notes principal investigator Dr. Michael A. Caligiuri, director of Ohio State’s Comprehensive Cancer Center and CEO of the James Cancer Hospital and Solove Research Institute. “In fact, we show that using an antibody to block interleukin-15 prevents large granular lymphocyte leukemia development in this mouse model.”

JCI online early table of contents: March 1, 2011

EDITOR’S PICK – DREADD-ing your next meal

In the face of the growing obesity epidemic, much research has focused on the neuronal control of feeding behavior. Agouti-related protein (AgRP) neurons express three proteins that have been implicated in changes in energy balance, but the studies linking AgRP neurons to feeding behavior have produced mixed results.

To directly analyze the role of AgRP neurons, Bradford Lowell and colleagues, at Beth Israel Deaconess Medical Center in Boston, used DREADD technology (designer receptors exclusively activated by designer drugs) to specifically control the activation and deactivation of this population in mice. They found that chronic stimulation of AgRP neurons induced weight gain related to an increase in food intake. Similarly, inhibition of this neuronal population inhibited food intake. Furthermore, stimulation of AgRP neurons induced an intense, unrelenting food seeking behavior. The researchers believe that this study demonstrates that AgRP neurons are critical regulators of a behavioral program that drives individuals to find and consume food.

TITLE: Rapid, Reversible Activation of AgRP Neurons Drives Feeding Behavior in Mice

AUTHOR CONTACT:

Bradford B. Lowell

Beth Israel Deaconess Medical Center, Boston, MA, USA

Phone: 617 667-5954; Fax: 617 667-2927; E-mail: blowell@bidmc.harvard.edu

View this article at: http://www.jci.org/articles/view/46229?key=09789853ca520550840b

METABOLISM – New mechanism explains the role of growth hormone in fatty liver

Non-alcoholic fatty liver disease (NAFLD) is a common condition that is linked to obesity and insulin resistance. If left untreated, this build up of fat deposits within the liver cells can lead to fibrosis and scarring of the organ. Although not completely understood, aberrant growth hormone (GH) signaling is thought to contribute to the development of this disorder, as genetic deletion of the GH receptor in the livers of mice results in the development of fatty liver.

In new research, Ethan J. Weiss and colleagues, of the University of California, San Francisco, further investigated the role of GH signaling in NAFLD by generating mice in which JAK2- the intracellular mediator of GH signaling- was genetically deleted in the liver. They found that these mutant mice had increased serum GH which was responsible for the breakdown of fats into free fatty acids. In addition, the livers of mutant mice had increased expression of the transcription factor PPAR? and its target the fatty acid transporter Cd36. Remarkably, treating the mutant mice with an inhibitor of PPAR? improved the fatty liver phenotype. This work explains the mechanism by which disrupted GH signaling leads to NAFLD, as well as raises important questions regarding the safety of JAK2 inhibitors- currently used as therapeutics in some blood cancers- in human patients.

TITLE: Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

AUTHOR CONTACT:

Ethan Weiss

UCSF, San Francisco, CA, USA

Phone: 415-514-0819; Fax: 415-502-7949; E-mail: ethan.weiss@ucsf.edu

View this article at: http://www.jci.org/articles/view/42894?key=7de0e66dd56958dee949

ONCOLOGY – New therapy could stress out cancer cells

The rapid growth of cancer cells is due, in part, to successful adaptation to stressful environments. Cells respond to stresses, such as the accumulation of misfolded protein, by activating genes that help the cell restore homeostasis and survive, but paradoxically, they may also promote apoptosis if the stress is unresolved. This so-called unfolded protein response (UPR) functions in multiple cellular locations, including the endoplasmic reticulum and the mitochondria.

In this paper, researchers led by Dario Altieri, at the Wistar Institute Cancer Center in Philadelphia, investigated the role of UPR-modulating factors called heat shock proteins (specifically the HSP90 family) in the mitochondria. They found that treating brain tumor cells with a pharmacological inhibitor of mitochondrial HSP90s induced mitochondrial UPR signaling followed by cell death via a process called autophagy. Furthermore, inhibition of mitochondrial HSP90 sensitized several different kinds of tumor cells (including breast and prostate) to an apoptosis-inducing agent that currently being investigated as a cancer therapeutic. The researchers believe that these studies suggest that targeting the mitochondrial UPR pathway may be broadly beneficial in cancer therapy.

TITLE: Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells

AUTHOR CONTACT:

Dario Altieri

The Wistar Institute, Philadelphia, PA, USA

Phone: 215-495-6970; Fax: 215-495-6971; E-mail: daltieri@wistar.org

View this article at: http://www.jci.org/articles/view/44855?key=123d7aef14e1a423cc02

ONCOLOGY – Mouse model explains the role of cancerous protein in blood stem cells

Acute promyelocytic leukemia (APL) is a blood cancer that is most common in young adults; untreated, it has a 100% mortality rate. Most cases of APL are caused by a chromosomal translocation that results in the fusion of the promyelocytic leukemia gene with the retinoic receptor alpha gene generating the novel protein PML-RARA. This fusion protein is thought to inhibit the differentiation of some types of blood cells, but how its expression results in cancer is not fully understood.

In this paper, Timothey Ley and colleagues, at Washington University in St. Louis recapitulated the human disease in mice by expressing PML-RARA from the endogenous PML locus. The researchers noted an expansion of hematopoietic cells in these mice, suggesting that the fusion protein promoted continuous self-renewal of these cells. Furthermore, cells expressing the mutant protein had a competitive growth advantage, which predisposed them to acquire the secondary mutations necessary for the progression to cancer. The researchers believe that this mouse model provides new insights into the pathophysiology of APL in humans.

TITLE: PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

AUTHOR CONTACT:

John Welch

Washington University in Saint Louis University, St. Louis, MO, USA

Phone: 314-362-8832; Fax: 314-362-9333; E-mail: jwelch@dom.wustl.edu

View this article at: http://www.jci.org/articles/view/42953?key=0fd7def14340b8beb83e

INFECTIOUS DISEASE – Tuberculosis bacteria uses membrane vesicles to modulate immune responses

The World Health Organization estimates that one third of the world population is infected with the bacteria that cause TB, Mycobacterium tuberculosis (Mtb), though only a small percentage of those actually become ill. The immune response to Mtb in the host is mediated by signaling through toll-like receptors (TLRs); the bacteria secrete lipoproteins and glycolipids that bind to the TLRs, activating immune cells to kill the invading bacteria. However, activation of TLR2 within macrophages has also been implicated in allowing Mtb to inhibit the innate immune response. In addition, how these bacteria release the TLR ligands is unknown.

Some pathogenic bacteria deliver ligands to host cells using membrane vesicles (MVs), which can also contain toxins and other molecules important for pathogenesis. In this paper, Dr. Arturo Casadevall and his team at the Albert Einstein College of Medicine in the Bronx, New York found that Mtb and other related mycobacterium species also release MVs. Analysis of the proteins within these vesicles revealed that only the MVs from virulent bacteria contain TLR2 agonists, and the researchers found that MVs triggered immune responses in mice in a TLR2-dependent manner. The researchers hope that their findings may reveal new pathways to target in the development of tuberculosis therapeutics and vaccines.

TITLE: Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice

AUTHOR CONTACT:

Rafael Prados-Rosales

Albert Einstein College of Medicine, Bronx, NY, USA

Phone: 718-430-3730; Fax: ; E-mail: rprados@aecom.yu.edu

View this article at: http://www.jci.org/articles/view/44261?key=f604fcb8954241baed57

DEVELOPMENTAL BIOLOGY – Eya1 and Six1 help you put your best face forward

Deletions in chromosome 22 are a rare congenital condition that result in characteristic craniofacial malformations and heart defects, collectively called del22q11 syndromes. One of the genes deleted in del22q11 patients is T-box transcription factor 1 (Tbx1), which is required for the proliferation of muscle cells during heart and craniofacial development. In fact, the genes required for normal heart muscle development also contribute to the differentiation of the muscles that control facial expressions and jaw movement, suggesting that that disruption of a single pathway may explain the spectrum of defects observed in these patients. Fibroblast growth factor 8 (FGF8) is not deleted in this disease, but aberrant FGF8 signaling has been linked to the associated developmental abnormalities.

In new research, Sean Li and colleagues, at Children’s Hospital in Boston, investigated the role of another transcription factor Six 1, and its coactivator Eya1 in cardiac and craniofacial development. They found that the Six1 and Eya1 genes were required for normal patterning of the heart in mice, and that genetic deletion of either of them resulted a developmental phenotype that was similar to that seen in mice lacking Tbx1 or Fgf8. Furthermore, they found that Six1 and Eya1 cooperate to activate transcription of the Fgf8 gene, and that Tbx1 acts genetically upstream of Six1 and Eya1. The researchers believe that these findings reveal a new genetic pathway involved in cardiac and craniofacial development, and indicate that dysregulation of Six1 and Eya1 may contribute to the pathogenesis of del22q11 syndromes.

TITLE: A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis

AUTHOR CONTACT:

Sean Li

The Manton Center for Orphan Disease Research, Children’s Hospital Boston,, Boston, MA, USA

Phone: 617 919 2703; Fax: 617 730 0530; E-mail: Sean.Li@childrens.harvard.edu

View this article at: http://www.jci.org/articles/view/44630?key=fb3b38a840e8144ac33a

HEPATOLOGY – Heavy metal does mitochondrial damage in Wilson Disease

Wilson Disease (WD) is a rare, fatal genetic disorder in which mutations in a copper transporter gene result in massive copper overload in the liver. It is not clear how the accumulation of copper in liver cells (hepatocytes) leads to liver failure, but it has been previously reported that the mitochondria in hepatocytes from WD patients are structurally abnormal.

In new research, Hans Zischka and colleagues, of the Helmholtz center in Munich, Germany, investigated the effect of copper accumulation on mitochondria in a rat model of WD. They found that high copper levels induced structural changes in mitochondria that preceded liver failure, and that oxidative damage- previously thought to be one of primary determinants of WD- was undetectable before animals displayed disease symptoms. Copper overload resulted in crosslinking of mitochondrial membrane proteins, and importantly, this effect was reversible when rats were treated with copper chelating agents. The researchers believe that these studies more clearly define the molecular pathology of WD.

TITLE: Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease

AUTHOR CONTACT:

Hans Zischka

Helmholtz Center Munich, Neuherberg, , DEU

Phone: +49-89-3187-2663; Fax: ++49-89-3187-3449; E-mail: zischka@helmholtz-muenchen.de

View this article at: http://www.jci.org/articles/view/45401?key=3b90a7fad385adc2f871

HEPATOLOGY – A microRNA is critical for iron homeostasis

Iron is critical for the transport of oxygen in the blood, and thus the system that maintains iron homeostasis is highly regulated. Disturbance of this system leads to serious illness including anemia and iron overload syndromes such as hereditary hemochromatosis. Most of the body’s iron stores are in the liver, and that organ also produces the hormone hepcidin, which maintains iron homeostasis by inhibiting iron absorption in the intestine and iron release from macrophages.

In this paper, scientists from the laboratories of Martina U. Muckenthaler of the University of Heidelberg, Germany and Matthias W. Hentze, of the European Molecular Biology Laboratory in Heidelberg, investigated new mechanisms that might regulate hepcidin. They found that a microRNA, miR-122, was an important regulator of hepcidin levels, and functioned by targeting known activators of hepcidin expression. Inhibiting miR-122 in mice resulted in increased hepcidin levels and liver and plasma iron deficiency. This work is the first to implicate a miRNA in iron homeostasis, and the researchers believe miR-122 may be a viable therapeutic target in human diseases of this system.

TITLE: The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice

AUTHOR CONTACT:

Martina Muckenthaler

Department of Pediatric Oncology of the University of Heidelberg, Heidelberg, , DEU

Phone: +49 (0) 6221 568026; Fax: +49 (0) 6221 564580; E-mail: muckenth@embl-heidelberg.de

View this article at: http://www.jci.org/articles/view/44883?key=c4d1bebe95c313780718

HEMATOLOGY – NKp46 marks the spot in T-LGL leukemia

T cell large granular lymphocyte (T-LGL) and NK leukemias are rare forms of blood cancer. IL-15 is a cytokine required for the normal survival and expansion of some immune cells including NK cells and memory T cells, and its overexpression is implicated in the development of both of these diseases. Mice that overexpress IL-15 spontaneously develop NK or T-LGL leukemia.

To investigate the mechanism of this process, Michael A. Caligiuri, Jianhua Yu and their team at Ohio State University in Columbus, Ohio examined the T cell populations in these mutant mice. They found that mice expressing excess IL-15 had an expanded population of T cells that express the cytoxicity receptor NKp46, an NK cell marker, and that all of the leukemic cells in mice with T-LGL leukemia expressed NKp46. These NKT cells were more active and more responsive to cytokine simulation, and further studies suggested that it was malignant transformation of this small population that accounted for the development of disease. Remarkably, treatment of IL-15 expressing mice with an antibody that targeted this T-cell subset prevented the development of leukemia. The researchers also identified a similar subset of T-cells in human samples, and believe that this work identifies a unique subset of immune cells that are susceptible to cancerous transformation in the presence of high levels of IL-15. They hope that these data may help in the design and targeting of new drugs for this as yet incurable disease.

TITLE: NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human

AUTHOR CONTACT:

Michael Caligiuri

The Ohio State University, Columbus, OH, USA

Phone: (614) 293-7521; Fax: (614) 293-7522; E-mail: michael.caligiuri@osumc.edu

View this article at: http://www.jci.org/articles/view/43242?key=ddd1b09f16df1a49a3b7

Study links vitamin D to lung cancer survival

ANN ARBOR, Mich. ? Recent research suggests vitamin D may be able to stop or prevent cancer. Now, a new study finds an enzyme that plays a role in metabolizing vitamin D can predict lung cancer survival.

The study, from researchers at the University of Michigan Comprehensive Cancer Center, suggests that this enzyme stops the anti-cancer effects of vitamin D.

Levels of the enzyme, called CYP24A1, were elevated as much as 50 times in lung adenocarcinoma compared with normal lung tissue. The higher the level of CYP24A1, the more likely tumors were to be aggressive. About a third of lung cancer patients had high levels of the enzyme. After five years, those patients had nearly half the survival rate as patients with low levels of the enzyme.

Researchers then linked this to how CYP24A1 interacts with calcitriol, the active form of vitamin D. CYP24A1 breaks down calcitriol, which has a normal and crucial role when kept in check. But when levels of CYP24A1 climb, the enzyme begins to hinder the positive anti-cancer effects of vitamin D.

Results of the study appear in Clinical Cancer Research.

Previous studies have linked low levels of vitamin D to a higher incidence of cancer and worse survival. Researchers are looking at using vitamin D to help prevent lung cancer from returning and spreading after surgery. This new study suggests the possibility of using CYP24A1 levels to personalize this approach to those likely to benefit most.

“Half of lung cancers will recur after surgery, so it’s important to find a way to prevent or delay this recurrence. A natural compound like vitamin D is attractive because it has few side effects, but it’s even better if we can determine exactly who would benefit from receiving vitamin D,” says study author Nithya Ramnath, M.D., associate professor of internal medicine at the U-M Medical School.

Researchers also are working to identify drugs that block CYP24A1. Blocking the enzyme would reinstate the positive anti-cancer effects of vitamin D, suggesting that this inhibitor could potentially be combined with vitamin D treatments.

NOTE: Current recommendations call for 600-800 IU of vitamin D daily, depending on age. Studies looking at vitamin D in lung cancer are testing medically administered doses 200 times what could be taken by mouth naturally. Taking large amounts of vitamin D supplements is not currently recommended to prevent or treat lung cancer.

Lung cancer statistics: 222,520 Americans will be diagnosed with lung cancer this year and 157,300 will die from the disease, making it the biggest cancer killer, according to the American Cancer Society

Additional U-M authors: Guoan Chen, So Hee Kim, Amanda N. King, Lili Zhao, Robert U. Simpson, Paul J. Christensen, Zhuwen Wang, Dafydd G. Thomas, Thomas J. Giordano, Lin Lin, Dean E. Brenner, David G. Beer

Funding: National Institutes of Health

Disclosure: None

Reference: Clinical Cancer Research, Vol. 17, No. 4, pp. 817-826

Resources:

U-M Cancer AnswerLine, 800-865-1125

U-M Comprehensive Cancer Center, www.mcancer.org

Clinical trials at U-M, www.UMClinicalStudies.org

For more information, contact:

Nicole Fawcett, nfawcett@umich.edu, or

Margarita B. Wagerson, mbauza@umich.edu

734-764-2220