Navigation Links
Subtle changes in PTEN tumor suppressor gene can determine cancer susceptibility

BOSTON It is an accepted fact that genetics play a key role in a person's susceptibility to cancer, and that throughout life, mutations can cause damage to tumor suppressor genes (TSGs) further increasing the chances of developing cancerous tumors.

Now a new study led by scientists at Beth Israel Deaconess Medical Center (BIDMC) demonstrates that even subtle changes in expression of the PTEN tumor suppressor gene can significantly increase cancer susceptibility in specific tissues, suggesting that environmental factors, such as diet or exposure to carcinogens, may have a more dramatic influence on tumor development than previously recognized. Appearing in this week's Advance On-line issue of Nature Genetics, the findings propose a new model for the role of tumor suppressor genes in the onset of cancer and could prove valuable in the development of diagnostic tests targeted to these gene alterations.

"More than 30 years ago, it was proposed that a person's susceptibility to cancer was dependent on a 'two-hit' model," explains Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. This meant that there had to be two genetic alterations of a single tumor suppressor gene (TSG) to activate tumor development one gene would be missing from birth, while the second would be lost to other factors during one's lifetime.

"Our study adds another dimension to this Knudsonian model [so-named for its creator, cancer geneticist Alfred Knudson] demonstrating that cancer susceptibility can be driven in specific tissues by a progressive -- but slight -- continuum reduction in tumor suppressor levels," explains Pandolfi. "Consequently, subtle modulation of TSG levels can result in increased cancer susceptibility. This implies that any factor that affects PTEN levels chemicals, diet, other carcinogens could increase tumor susceptibility, even in the absence of a full blown genetic mutation."

Tumor suppressor genes function to slow down cell division, repair DNA and help alert damaged cells when it is time to die, and PTEN is one such example. (In addition to preventing uncontrolled cell growth, PTEN is also responsible for controlling cell movement or migration, controlling the adhesion of cells to surrounding tissues and helping to control the formation of new blood cells.) But, when TSGs are absent or malfunctioning as is the case of a genetic mutation cells can multiply too quickly, growing out of control and leading to the development of cancerous tumors.

In recent years, with the advent of functional genomics, the idea that subtle changes in TSG levels could influence tumor development had been proposed but not formally investigated. To test this hypothesis, the Pandolfi team created a mouse model of PTEN that expressed the gene at approximately 80 percent of total levels. Next, they used a gene targeting approach which drives a transcriptional interference of the PTEN gene, resulting in inefficient protein production. The authors report that the presence of one targeted allele resulted in approximately 80 percent of PTEN expression relative to the normal level of PTEN expressed in specific tissues in this case, mammary gland tissue. And, as predicted, the scientists subsequently identified an increased incidence of mammary tumors in these mice, and through a careful histopathological and molecular analysis were able to demonstrate that mammary tumors maintained both the targeted and wild-type PTEN alleles intact.

"These mice showed mammary cancer at a high incidence and in the absence of further alterations to the PTEN gene," explains Pandolfi. "This confirms that the PTEN gene is a 'quasi-insufficient' tumor suppressor, such that even a subtle 20 percent decrease in gene expression is sufficient to impair its full tumor-suppressive activity."

This discovery, say the authors, is tremendously relevant for how genetic alterations in cancer are detected, studied, evaluated and treated. "From a diagnostic perspective, our findings encourage the implementation of quantitative methods to evaluate cancer gene expression levels, and the design of therapies oriented to target these alterations," they write. Adds Pandolfi, "Our immediate aim is to develop a genetic test to be used for the screening of patients at risk of developing breast cancer. Such a test might also be useful in predicting the outcome of certain treatments [i.e. Trastuzumab] for breast cancer patients."


Contact: Bonnie Prescott
Beth Israel Deaconess Medical Center

Related biology news :

1. New technique reveals subtle force-induced changes in biomolecules conformation
2. Old developmental pathways spawn revolutionary evolutionary changes
3. New study shows fish respond quickly to changes in mercury deposition
4. New study shows fish respond quickly to changes in mercury deposition
5. Great Plains historical stability vulnerable to future changes
6. Tolerance to inhalants may be caused by changes in gene expression
7. A new explanation for evolutionary changes in genetic sex-determination systems
8. Hearing changes how we perceive gender
9. UC Davis bird-flu expert calls for changes in early-warning system
10. Elevated carbon dioxide changes soil microbe mix below plants
11. Humans have caused profound changes in Caribbean coral reefs
Post Your Comments:
(Date:11/17/2015)... Pressure BioSciences, Inc. (OTCQB: PBIO) ("PBI" and ... of broadly enabling, pressure cycling technology ("PCT")-based sample preparation ... it has received gross proceeds of $745,000 from an ... "Offering"), increasing the total amount raised to date in ... are expected in the near future. ...
(Date:11/12/2015)... 2015  Arxspan has entered into an agreement ... for use of its ArxLab cloud-based suite of ... partnership will support the institute,s efforts to electronically ... information internally and with external collaborators. The ArxLab ... the Institute,s electronic laboratory notebook, compound and assay ...
(Date:11/10/2015)...  In this report, the biomarkers market ... type, application, disease indication, and geography. The ... consumables, services, software. The type segments included ... biomarkers, and validation biomarkers. The applications segments ... drug discovery and development, personalized medicine, disease ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... ... 2015 , ... Copper is an essential micronutrient that all ... copper is also toxic to cells. With a $1.3 million award from the ... a systematic study of copper in the bacteria Pseudomonas aeruginosa (P. aeruginosa), a ...
(Date:11/24/2015)... PUNE, India , November 24, 2015 ... to a new market research report "Oligonucleotide Synthesis Market ... Equipment), Application (PCR, Gene Synthesis, Diagnostic, DNA, RNAi), End-User ... to 2020", published by MarketsandMarkets, the market is expected ... 1,078.1 Million in 2015, at a CAGR of 10.1% ...
(Date:11/24/2015)... --> --> ... by Transparency Market Research, the global non-invasive prenatal testing ... 17.5% during the period between 2014 and 2022. The ... Analysis, Size, Volume, Share, Growth, Trends and Forecast 2014 ... to reach a valuation of US$2.38 bn by 2022. ...
(Date:11/24/2015)... ... November 24, 2015 , ... In harsh industrial processes, the ... in-line sensors can represent a weak spot where leaking process media is a ... sensor housings , which are designed to tolerate extreme process conditions. They combine ...
Breaking Biology Technology: