Public Release:  JCI table of contents: July 12, 2007

Journal of Clinical Investigation


Src inhibitors may prove beneficial in breast cancer therapy

Estrogen, which binds estrogen receptor alpha (ER-alpha), is a risk factor for breast cancer development. However, one-third of new breast cancers lack detectable ER-alpha. These ER-alpha-negative cancers are more aggressive and have a worse prognosis than do ER-alpha-positive breast cancers, and have been thought to be estrogen independent. In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Joyce Slingerland and colleagues from the University of Miami shed further light on the mechanisms regulating ER-alpha expression levels during breast cancer.

In their study of 250 primary breast cancers, the authors found that ER mRNA levels overlap considerably between ER-alpha-positive and ER-alpha-negative breast cancers. This lack of correlation between ER-alpha mRNA and protein levels pointed to the existence of important post-transcriptional control of ER-alpha expression. They found that ER-alpha-negative primary breast cancers and cell lines showed increased levels and/or activity of the protein Src, which cooperates with estrogen to activate ER-alpha breakdown via proteolysis. In line with this finding, Src inhibition was shown to impair estrogen-stimulated ER-alpha proteolysis. The data raise the possibility that for at least a subset of ER-alpha-negative breast cancers, Src may stimulate estrogen-dependent ER-alpha degradation, resulting in a lack of ER-alpha detection, and more aggressive tumor growth. The authors conclude that their study provides a rationale for the use of Src inhibitors in breast cancer therapy.

TITLE: Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer

Joyce M. Slingerland
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone : (305) 243-7265; Fax: (305) 243-4787; E-mail:

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The clot thickens: protein interaction is a drug target for blood clot prevention

After a blood vessel in injured, platelets cluster together to plug the site of injury in the form of a blood clot (thrombus). In arterial disease, altered platelet aggregation can block blood vessels and cause heart attack or stroke. Platelet aggregation involves the binding of many molecules to platelet integrin alpha-IIb beta 3, and blockade of this binding is effective in the prevention of blood clots. However, chronic use of oral drugs that block alpha-IIb beta 3 activation have not proved beneficial in preventing recurrent blood clots. In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Mark Ginsberg and colleagues from the University of California San Diego show that the binding of the protein talin to alpha-IIb beta 3 is critical for integrin activation in mice, and that selective disruption of the talin-alpha-IIb beta 3 interaction protects mice from pulmonary thromboembolism - the formation of blood clots in the vessel that carries blood from the heart to the lungs. Furthermore, this blockade results in very little pathological bleeding, which can often occur when the clotting process is disrupted. The results suggest that modulation of the interaction between talin and alpha-IIb beta 3 could be an attractive strategy for the development of future anti-thrombotic drugs, with a reduced risk of pathological bleeding.

TITLE: The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation

Mark H. Ginsberg
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 822-6432; Fax: (858) 822-6458; E-mail:

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Eap1 in the brain regulates the female reproductive cycle

The onset of puberty and maintenance of the female reproductive cycle are events controlled by neurons in the hypothalamus that secrete gonadotropin-releasing hormone (GnRH). How signaling to these neurons is controlled remains unclear. In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Sergio Ojeda and colleagues from Oregon Health & Science University report that the gene enhanced at puberty 1 (EPA1) acts as a regulator of the neuronal signaling that controls female reproductive function.

The authors found that EPA1 expression was selectively increased at puberty in the hypothalamus in monkeys, rats, and mice. They also showed that the protein product of EPA1 was expressed in neurons involved in the control of reproduction, and that EAP1 activated GnRH. The authors went on to show that inhibition of EPA1 expression in the rat hypothalamus delayed the onset of puberty and disrupted estrous in these animals. The data suggest that EPA1 is an important regulator acting within the brain and contributes to the control of female reproductive function.

TITLE: Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

Sergio R. Ojeda
Oregon Health & Science University, Beaverton, Oregon, USA.
Phone : (503) 690-5302; Fax: (503) 590-5384; E-mail:

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Which T cell types drive the autoimmune response in multiple sclerosis?

In multiple sclerosis (MS), the myelin that surrounds the axons of nerve cells is attacked by the body's own T cells, resulting in slowed and disrupted nerve impulses and, ultimately, axon loss. Myelin basic protein (MBP) is a major component of the myelin sheath and when used as an antigen will induce experimental autoimmune encephalitis (EAE) in mice, which is used as an animal model of human MS. Interestingly, myelin-specific T cells are found in both healthy individuals as well as patients with MS, thus researchers have been working to determine what specific characteristic of these destructive T cells is dominant in driving the development of EAE/MS. In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Eli Sercarz and colleagues from the Torrey Pines Institute for Molecular Studies immunized mice with an epitope of MBP known as Ac1-9, which resulted in a single episode of EAE in these animals, followed by recovery and resistance to any reinduction of disease. The authors then went on to characterize the Ac1-9-specific T cells present during the induction, onset, and recovery from disease. They identified two distinct subsets of T cells, or clonotypes, soon after immunization and prior to disease onset: BV8S2/BJ2S7 and BV16/BJ2S5. The BV8S2/BJ2S7 clonotype was found in far greater excess, disappeared with disease recovery, and was found to transfer disease to other healthy mice. The second clonotype, BV16/BJ2S5, persisted following recovery, consistent with the hypothesis that the other, BV8S2/BJ2S7 T cell clonotype, is the driver of disease and necessary for EAE/MS persistence. The identification of this T cell subset suggests that these cells may be critical targets valuable to the design of therapies for autoimmune diseases such as MS.

TITLE: A public T cell clonotype within a heterogeneous autoreactive repertoire is dominant in driving EAE

Eli E. Sercarz
Torrey Pines Institute for Molecular Studies, San Diego, California, USA.
Phone: (858) 455-3824; Fax: (858) 455-3715; E-mail:

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