More clues to causes of breast cancer: Hyperactivation of Akt and overexpression of IKBKE observed in 50 percent of human cancers

ScienceDaily (Oct. 27, 2011) — Publishing in the current issue of The Journal of Biological Chemistry, researchers at Moffitt Cancer Center in Tampa, Fla., have discovered additional mechanisms of "Akt" activation and suggest a component of that activation mechanism -- inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) -- could be targeted as a therapeutic intervention for treating cancer.

Akt, also known as protein kinase B, is one of about 500 protein kinases in the human genome. Kinases are known to regulate the majority of cellular pathways. Akt modifies other proteins chemically and regulates cell proliferation.

"Recent evidence suggests that IKBKE is an oncogenic kinase that participates in malignant transformation and tumor development," said Moffitt senior researcher and lead author Jin Q. Cheng, Ph.D., M.D. "Our study identified Akt as a bona fide substrate of IKBKE and IKBKE direct activation of Akt independent PI3K and revealed a functional link between IKBKE and Akt activation in breast cancer."

Cheng's lab studies a variety of genetic alterations and their molecular mechanisms in both ovarian and breast cancer, particularly on their effect on the molecules that are regulated by Akt and the small molecule inhibitors of Akt.

"We found that inhibition of Akt suppresses IKBKE's oncogenic transformation," said Cheng. "This is significant because overexpression of IKBKE and activation of Akt has been observed in more than 50 percent of human cancers. Akt inhibitors targeting PH domain do not have inhibitory effect on IKBKE-induced Akt."

The researchers experimented with a variety of inhibitors currently being used in clinical trials.

The laboratory study utilized breast cancer cell lines from received from patient donors at Moffitt and cell lines received from Harvard University and Johns Hopkins University. The work was supported by a National Institutes of Health grant and a grant from the James and Esther King Biomedical Research Program.

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The above story is reprinted from materials provided by H. Lee Moffitt Cancer Center & Research Institute.

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Journal Reference:

J.-P. Guo, D. Coppola, J. Q. Cheng. IKBKE Protein Activates Akt Independent of Phosphatidylinositol 3-Kinase/PDK1/mTORC2 and the Pleckstrin Homology Domain to Sustain Malignant Transformation. Journal of Biological Chemistry, 2011; 286 (43): 37389 DOI: 10.1074/jbc.M111.287433

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Lung stem cells offer therapeutic clues

ScienceDaily (Oct. 27, 2011) — Guided by insights into how mice recover after H1N1 flu, researchers at Harvard Medical School and Brigham and Women's Hospital, together with researchers at A*STAR of Singapore, have cloned three distinct stem cells from the human airways and demonstrated that one of these cells can form into the lung's alveoli air sac tissue. What's more, the researchers showed that these same lung stem cells are rapidly deployed in a dynamic process of lung regeneration to combat damage from infection or chronic disease.

"These findings suggest new cell- and factor-based strategies for enhancing lung regeneration following acute damage from infection, and even in chronic conditions such as pulmonary fibrosis," said Frank McKeon, professor of cell biology at Harvard Medical School. Other senior authors on the paper include Wa Xian of the Institute of Medical Biology in Singapore and Brigham and Women's Hospital, and Christopher Crum, Director of Women's and Perinatal Pathology at Brigham and Women's Hospital. The researchers worked as part of an international consortium involving scientists from Singapore and France.

The findings will be reported in the Oct. 28 issue of Cell.

For many years, clinicians have observed that patients who survive acute respiratory distress syndrome (ARDS), a form of airway damage involving wholesale destruction of large regions of lung tissue, often recover considerable pulmonary function within six to 12 months. But researchers did not know whether that recovery was due to lung regeneration or to some other kind of adaptive remodeling.

"This study helps clear up the uncertainty," said McKeon. "We have found that the lungs do in fact have a robust potential for regeneration, and we've identified the specific stem cells responsible."

To probe the potential for lung regeneration, Xian, McKeon and colleagues infected mice with a sublethal dosage of a virulent strain of H1N1 influenza A virus. After two weeks of infection, these mice showed a loss of nearly 60 percent of tissue in the lung air sacs after two weeks of infection, but -- remarkably -- by three months, the lungs appeared completely normal by all histological criteria.

These findings demonstrated true lung regeneration, but raised the question of the nature of the stem cells underlying this regenerative process.

Adapting the methods for cloning epidermal skin stem cells pioneered by Howard Green, the George Higginson Professor of Cell Biology at HMS and the 2010 Warren Alpert Foundation Prize recipient, the researchers cloned stem cells from the lung airway in a dish and watched as they differentiated to unusual structures with gene profiles similar to alveoli, the cells in the lung's air sacs.

"This was startling to us," Xian said, "and even more so as we observed the same stem cell populations involved in alveoli formation during the peak of H1N1 infections in mice." The researchers genetically traced the formation of new alveoli to a discrete population of stem cells in the fine endings of the conducting airways that rapidly divide in response to infection and migrate to sites of lung damage.

The scientists were intrigued when molecular dissection of these incipient alveoli revealed the presence of an array of signaling molecules known to control cell behavior, suggesting the possibility that these molecules coordinate the regeneration process itself.

Currently the team is testing the possibility that the secreted factors they observed might promote regeneration, suggesting a therapeutic approach for conditions such as chronic obstructive pulmonary disease and even asthma. They also foresee the possibility that these distal airway stem cells could contribute to repairing lungs scarred by irreversible fibrosis, conditions resistant to present therapies.

This work was supported by the National Heart, Lung, and Blood Institute, the Institute of General Medical Sciences, the National Cancer Institute, and the Defense Advanced Research Projects Agency.

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Journal Reference:

Pooja A. Kumar, Yuanyu Hu, Yusuke Yamamoto, Neo Boon Hoe, Tay Seok Wei, Dakai Mu, Yan Sun, Lim Siew Joo, Rania Dagher, Elisabeth M. Zielonka, De Yun Wang, Bing Lim, Vincent T. Chow, Christopher P. Crum, Wa Xian, Frank McKeon. Distal Airway Stem Cells Yield Alveoli In Vitro and during Lung Regeneration following H1N1 Influenza Infection. Cell, 28 October 2011 DOI: 10.1016/j.cell.2011.10.001

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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