New class of proteins allows breast cancer cells to evade Tyrosine Kinase Inhibitors
Aberrant regulation of cell growth pathways is required for normal cells to become cancerous, and in many types of cancer, cell growth is driven by a group of enzymes known as receptor tyrosine kinases (RTKs). The RTK epidermal growth factor receptor (EGFR) is overexpressed in over 30% of breast cancers; however, drugs that target RTKs, known as tyrosine kinase inhibitors (TKIs) have not been effective in treating breast cancer. Researchers believe that the cancer cells escape TKIs by circumventing the RTKs and utilizing other enzymes that are not TKI-sensitive.
In the current issue of the Journal of Clinical Investigation, two groups identify a pair of related oncogenes, FAM83A and B, which allow breast cancer cells to survive TKI treatment. Researchers led by Mina Bissell at the Lawrence Berkeley National Laboratory in Berkeley, CA performed a screen of human breast cancer cell lines to identify genes that make cancer cells resistant to EGFR TKIs. Bissell and colleagues determined that increased expression of FAM83A increases proliferation and invasion, while decreased expression delays tumor growth in mice and renders cancer cells sensitive to TKIs. At Case Western Reserve Medical School in Cleveland, OH, Mark Jackson and colleagues identified FAM83B as a gene that allows normal human mammary cells to become malignant. Further, expression of FAM83A and B in human tumors was correlated with decreased overall survival. Taken together, these studies identify two genes that may serve as novel therapeutic targets. In a companion piece, Steven Grant of the Medical College of Virginia discusses the impact of this research on the development of strategies to overcome resistance to currently available TKIs.
TITLE:
FAM83B mediates EGFR- and RAS-driven oncogenic transformation
AUTHOR CONTACT:
Mark Jackson
Case Western Reserve University School of Medicine, Cleveland, OH, USA
Phone: 216-368-1276; E-mail: mwj7@case.edu
View this article at: http://www.jci.org/articles/view/60517?key=54f5069a5953e8a04eee
ACCOMPANYING ARTICLE
TITLE:
FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice
AUTHOR CONTACT:
Mina Bissell
Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Phone: 510 486-4365; E-mail: mjbissell@lbl.gov
View this article at: http://www.jci.org/articles
ACCOMPANYING COMMENTARY
TITLE:
FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators
AUTHOR CONTACT:
Steven Grant
Medical College of Virginia, Richmond, VA, USA
E-mail: stgrant@vcu.edu
View this article at: http://www.jci.org/articles
Even bones get fatter with age: changes in bone marrow stem cell differentiation may contribute to osteoporosis
Osteoporosis occurs when the balance between bone formation and resorption shifts in favor of resorption, leading to reduced bone mass and frail bones. Bone marrow stem cells, which are retained throughout life, are capable of becoming bone-forming cells, known as osteoblasts, or fat cells, known as adipocytes. Several recent studies have demonstrated that bone marrow stem cells from patients with osteoporosis are more likely to become adipocytes than osteoblasts compared with stem cells from patients with normal bone mass. Further, patients with osteoporosis have a greater number of adipocytes within their bones, causing researchers to wonder if the increased bone marrow fat is a consequence or a cause of osteoporosis.
The level of different growth factors present in bone marrow helps determine the fate of the bone marrow stem cells, and one particular growth factor, VEGF, is known to decrease with age. In this issue of the Journal of Clinical Investigation, researchers led by Bjorn Olsen at the Harvard School of Dental Medicine examined the effect of VEGF on bone marrow stem cell fate in mice. Mice lacking VEGF developed a condition similar to osteoporosis and had more adipocytes in their bones. These studies suggest that an age-related decrease in VEGF may contribute to osteoporosis in humans.
TITLE:
Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation
AUTHOR CONTACT:
Bjorn R. Olsen
Harvard School of Dental Medicine, Boston, MA, USA
Phone: 617-432-1874; Fax: 617-432-0638; E-mail: bjorn_olsen@hms.harvard.edu
View this article at: http://www.jci.org/articles
Calcium sensors in kidneys may help combat hypoparathyroidism
Calcium is required for the function of the nervous, muscular, and skeletal systems and must be maintained within a very narrow range in the blood. When blood calcium levels are too low, the parathyroid secretes parathyroid hormone (PTH), triggering increased absorption of dietary calcium in the intestines and removal of calcium from bones. When calcium levels are too high, calcium-sensing receptors (CaSR) on the parathyroid block the release of PTH and increase uptake of calcium by the kidneys for excretion in urine.
In addition to the parathyroid, CaSR are also found on kidney cells; however, it is unclear what role these calcium sensors play in calcium metabolism. In the current issue of the Journal of Clinical Investigation, researchers led by Pascal Houillier at the Hôpital Européen Georges Pompidou in Paris, uncovered a novel function of the CaSR in calcium metabolism. Using parathyroidectomized rats, Houillier and colleagues measured calcium excretion by the kidneys in the presence and absence of CaSR inhibitors. These studies are the first to show that CaSR can directly determine the level of calcium in the blood by altering calcium transport in the kidneys. Further, these studies suggest that CaSR inhibitors might be useful in treating patients suffering from hypoparathyroid disease.
TITLE:
PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor
AUTHOR CONTACT:
Pascal Houillier
INSERM, Paris, UNK, FRA
Phone: +33 1 44 41 37 14; Fax: +33 1 44 41 37 17; E-mail: pascal.houillier@egp.aphp.fr
View this article at: http://www.jci.org/articles
Treating blindness with DNA nanoparticles
Stargardt macular dystrophy is a genetic disease that causes juvenile blindness. In the most common form of the disease, a mutation occurs in the ABCA4 gene, which encodes for a protein that is expressed in the eye's photoreceptor cells and is required for the removal of lipofuscin, a toxic byproduct of the visual metabolic cycle. In patients with mutant ABCA4, lipofuscin accumulates in the photoreceptors, leading to retinal degeneration. Replacement of the defective ABCA4 gene could rescue the photoreceptors and provide a cure for Stargardt's disease.
In a recent issue of the Journal of Clinical Investigation, a research team at the University of Oklahoma Health Sciences Center in Oklahoma City describes a new method to replace the ABCA4 gene in mice. Researchers led by Muna Naash injected a DNA nanoparticle encoding ABCA4 directly into the retinas of the mice. The mice had detectable levels of ABCA4 for up to 8 months and had improved visual responses compared to untreated animals. These studies demonstrate that DNA nanoparticles may be a useful technology in the treatment of genetic diseases.
TITLE:
DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice
AUTHOR CONTACT:
Muna Naash
OUHSC, Oklahoma City, OK, USA
Phone: 405-271-2388; Fax: 405-271-3548; E-mail: muna-naash@ouhsc.edu
View this article at: http://www.jci.org/articles
A common tumor suppressor helps breast cancer cells survive metabolic stress
For more than a century, researchers have known that cancer cells use different methods to fuel themselves compared to normal cells and that these alterations in cancer cell metabolism contribute to tumor growth and progression. As tumors rapidly expand, many cells lose their moorings in the extracellular matrix that helps to hold normal cells in place. This unmooring prevents the cells from accessing normal energy sources such as glucose, resulting in metabolic stress. This metabolic stress kills normal cells, but cancer cells have evolved methods to compensate.
Researchers at Beth Israel Deaconess Medical Center in Boston have been working to identify molecules that help breast cancer cells survive metabolic stress. In a recent article in the Journal of Clinical Investigation, Pier Pandolfi and colleagues report that PML, a gene long considered a tumor suppressor, allows breast cancer cells to survive metabolic stress. Studies in breast cancer cells demonstrated that expression of PML helps cancer cells to suppress harmful metabolic pathways and help to stabilize the cancer cells as they detach and migrate. Analysis of human breast cancer tissues showed that expression of PML is correlated with reduced time to recurrence and poor prognosis, suggesting that PML may serve as a useful prognostic marker in breast cancer and a possible therapeutic target.
TITLE:
A metabolic pro-survival role for PML in breast cancer
AUTHOR CONTACT:
Arkaitz Carracedo
CIC biogune, Derio, , ESP
Phone: 34 94 406 1327; E-mail: acarracedo@cicbiogune.es
View this article at: http://www.jci.org/articles
Researchers identify specific immune cells as key players in artherosclerosis
Artherosclerosis is a chronic inflammatory disease of large and medium sized arteries where immune cells and low-density lipoprotein (LDL) accumulate to form plaques on the vessel wall. The plaques cause the arteries to harden and eventually become narrow and block the flow of blood. Various immune system responses contribute to the formation of artherosclerotice plaques, but we currently have a poor understanding of which immune cells and antigens are involved.
In a study in the current issue of the Journal of Clinical Investigation, researchers led by Klaus Ley at the La Jolla Institute for Allergy and Immunology in La Jolla, CA used live cell imaging techniques to track immune cells in normal and artherosclerotic mouse aortas. Ley and colleagues found that antigen interactions with a specific type of immune cell known as a CD4+ T cell led to the production of inflammatory factors and foam cell formation. These studies will lead to a better understanding of the underlying causes of artherosclerosis and will be essential in developing new therapies to treat the disease.
TITLE:
Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis
AUTHOR CONTACT:
Klaus Ley
La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Phone: (858) 752-6661; E-mail: klaus@liai.org
View this article at: http://www.jci.org/articles/view/61758?key=90195ae4e236363df7c2
Journal
Journal of Clinical Investigation