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JCI table of contents: Aug. 24, 2009

ONCOLOGY: Human breast cancer hit for six: key role for Six1 in tumor development and metastasis

Heide Ford and colleagues, at the University of Colorado School of Medicine, Aurora, have provided new insight into breast cancer development using mouse models and analysis of human cells, implicating the protein Six1 as central to this process.

Six1, a protein that plays a central role in development, is not expressed in the majority of adult cells other than cancer cells of several types, including breast cancer cells. In the first of two studies from the Ford laboratory, expression of human Six1 in mouse breast gland cells known as epithelial cells resulted in aggressive tumors. The tumors showed signs (including expression of the protein cyclin D1) of a cellular process known as EMT, which has been linked to the development of metastatic capability, and had increased numbers of cells with stem/progenitor characteristics, cells that have been linked to increased tumor progression and resistance to many therapies. In the second study, overexpression of Six1 in human breast cancer cell lines resulted in EMT, in part, via the ability of Six1 to increase signaling mediated by a soluble molecule known as TGF-beta. Importantly, these human cells showed enhanced ability to metastasize when transplanted into mice.

In both studies, human data indicated that these phenomena are not restricted to mouse models. First, while Six1 expression has been previously shown to be predictive of poor prognosis in individuals with breast cancer, Ford and colleagues found that coexpression of Six1 and cyclin D1 was an even better predictor of poor prognosis. Second, Six1 expression in human breast cancer tissue correlated with proteins indicative of TGF-beta signaling. Third, Six1 expression in human breast cancer correlated with shortened time to metastasis and relapse and with shortened overall survival. Finally, the authors suggest that Six1 expression is probably central to tumor development in other forms of cancer as it correlated with adverse outcomes in numerous other cancers, including cancers of the brain, cervix, prostate, colon, kidney, and liver.

In an accompanying commentary, Derek Radisky, at the Mayo Clinic, Jacksonville, discusses how the two papers compliment each other to provide new detailed understanding of the mechanisms by which Six1 promotes tumor development and metastasis. Information that it might be possible to translate for clinical benefit.

TITLE: Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

Heide L. Ford
University of Colorado School of Medicine, Aurora, Colorado, USA.
Phone: (303) 724-3509; Fax: (303) 724-3512; E-mail:

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TITLE: The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling

Heide L. Ford
University of Colorado School of Medicine, Aurora, Colorado, USA.
Phone: (303) 724-3509; Fax: (303) 724-3512; E-mail:

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TITLE: Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis

Derek C. Radisky
Mayo Clinic, Jacksonville, Florida, USA.
Phone: (904) 953-6913; Fax: (904) 953-0277; Email:

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CARDIOLOGY: Abnormal heartbeats caused by changes in ion channel density

Two independent studies have determined how changes in the density of different ion channels in the surface membrane of heart muscle cells can lead to life-threatening abnormal heartbeats. As Gail Robertson, at the University of Wisconsin Madison, discusses in an accompanying commentary, these important studies provide new insight into the complex array of mechanisms controlling our heartbeat and how they can be perturbed.

The coordinated contraction of heart muscle cells that ensures a normal heartbeat is controlled by an electrical current that passes from one heart muscle cell to the next and along a special conduction system within the heart. A block in conduction of this electrical current disrupts the heartbeat and is the most common cause of pacemaker implantation. Many diseases that cause conduction block, including progressive familial heart block type I (PFHBI), are inherited. Olaf Pangs and colleagues, at Universitt Hamburg, Germany, have now linked a mutation in the gene TRPM4 with PFHBI in 3 branches of a large South African Afrikaner pedigree with the disease. The TRPM4 gene is responsible for generating an ion channel that the authors found to be expressed at highest levels in a crucial region of the special conduction system within the human heart. Importantly, the PFHBI-associated mutation increased levels of the TRPM4 channel at the cell surface and blunted conduction of the electrical current.

A noninherited cause of an abnormal heartbeat is low levels of potassium (K+) in the blood, which can trigger life-threatening changes to the heartbeat. Shetuan Zhang and colleagues, at Queen's University, Ontario, have now determined in rabbits that low levels of potassium in the blood cause decreased levels of the IKr ion channel at the surface of rabbit heart muscle cells. Specifically, low levels of potassium caused increased internalization and degradation of the channels. Similarly, low levels of potassium in culture medium decreased levels of the human counterpart, HERG, in cell lines. These data provide insight into how a drop in levels of potassium in the blood can cause sudden cardiac death.

TITLE: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I

Olaf Pongs
Zentrum fr Molekulare Neurobiologie, Universitt Hamburg, Hamburg, Germany.
Phone: 49-40-7410-55082; Fax: 49-40-7410-55102; E-mail:

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TITLE: Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Shetuan Zhang
Queen's University, Kingston, Ontario, Canada.
Phone: (613) 533-3348; Fax: (613) 533-6880; E-mail:

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TITLE: Endocytic control of ion channel density as a target for cardiovascular disease

Gail A. Roberston
University of Wisconsin Madison, Madison, Wisconsin, USA.
Phone: (608) 265-3339; Fax: 608-265-7821; Email:

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GASTROENTEROLOGY: Bicarbonate linked to sticky mucus in cystic fibrosis

A hallmark of cystic fibrosis, a disease caused by mutations in the CTFR gene, is the accumulation of abnormally thick and sticky mucus in the lung, intestine, and various other organs. Although the accumulation of this mucus is thought likely to play a central role in the development of disease, how mutations in the CTFR gene lead to mucus accumulation have not been determined. However, Paul Quinton and colleagues, at the University of California at San Diego, La Jolla, have now provided insight into this issue by studying mouse small intestine segments ex vivo. In an accompanying commentary, Robert DeLisle, at the University of Kansas School of Medicine, Kansas City, highlights the importance of the study and the potential new take on how mutations in the CTFR gene lead to mucus accumulation and disease.

One of the functions of the CTFR protein generated by the nonmutated CTFR gene is to transport bicarbonate (HCO3) out of cells. In their study, Quinton and colleagues developed a new ex vivo system for monitoring mucus release from the mouse small intestine to investigate whether defects in this function of CFTR might affect mucus secretion. Although basal rates of mucus release were similar in the presence or absence of bicarbonate, mucus release stimulated by natural chemicals such as serotonin was markedly decreased in the absence of bicarbonate. Interestingly, in a mouse model of cystic fibrosis, mucus release stimulated by natural chemicals was minimal in the presence or absence of bicarbonate. The authors therefore suggest that normal mucus release requires concurrent bicarbonate secretion and that the abnormally thick and sticky mucus that characterizes cystic fibrosis might be caused by defective bicarbonate secretion.

TITLE: Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulatordependent bicarbonate secretion

Paul M. Quinton
University of California at San Diego, La Jolla, California, USA.
Phone: (619) 543-9635; Fax: (619) 543-5642; E-mail:

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TITLE: Pass the bicarb: The importance of HCO3 for mucin release

Robert C. De Lisle
University of Kansas School of Medicine, Kansas City, Kansas, USA.
Phone: (913) 588-2742; Fax: (913) 588-2710; Email:

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Contact: Karen Honey
Journal of Clinical Investigation

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