Many women drink alcohol whether it is beer, wine, or liquor and this consumption can increase the risk for developing breast caner. In 2002, the Collaborative Group on Hormonal Factors in Breast Cancer published a report clearly showing a link between alcohol consumption and increased risk of developing breast cancer. In this study, scientists reviewed data from over 153,000 women (over 58,000 women with breast cancer and 95,000 women without breast cancer) who participated in 53 different studies conducted worldwide. Of the several questions explored in this analysis, one focus was to evaluate what contribution alcohol consumption made to altering the risk of developing breast cancer. The overall conclusion was that alcohol consumption raises the risk of developing breast cancer by 7% when those that drink alcohol were compared with those who don’t.
Breast cancer isn’t just one disease. There are multiple forms that it can take: ductal carcinoma, lobular carcinoma, hormone sensitive (estrogen and progesterone receptor positive), hormone insensitive. Ductal and lobular carcinoma arise in different locations -- either in the ducts within the breast (hence ductal) or within the milk producing glands (lobular). Hormone sensitivity means that there is expression of the estrogen receptor and the cancer is responsive to hormones (estrogen and progesterone) or it doesn’t express the receptors and therefore doesn’t respond to hormones. Ductal carcinoma is the most common form (70% of all breast cancers), with lobular carcinoma accounting for 30% of the cases. In the 2002 study, the analysis was between alcohol consumption and the risk of developing any form of breast cancer.
This week, an interesting new article looked at alcohol and breast cancer risk in a new light. Investigators from the Fred Hutchinson Cancer Institute in Seattle explored if alcohol consumption alters the type of breast cancer and focused on whether drinking alcohol contributes to the development of a particular form of breast cancer or if it is more general, affecting multiple forms of cancer. Interestingly, this analysis demonstrated that alcohol consumption raised the risk of developing lobular carcinoma but did not alter the risk of developing ductal carcinoma. In fact, the researchers found that alcohol affected hormone sensitive (estrogen receptor positive) lobular cancer formation.
What does this mean? It shows that different subtypes of cancer respond differently. They develop as a result of different causes and are influenced by different factors. Specifically, alcohol affects the development of lobular but not ductal cancer and uses estrogen in that process. How this happens is still unclear, but these findings are quite intriguing. These findings will help to understand how lobular cancers form and how estrogen affects them. It could lead to new methods to detect these cancers and maybe to how to prevent them in the first place.
Monday, August 30, 2010
Friday, August 20, 2010
non-coding and microRNAs
You mentioned the intricacies of the genome. I have heard the the term non-coding RNA. How does that fit into the scheme of the genome?
Thank you for the topic suggestion!
In the 1990s a new player took the stage in scientific research, microRNAs. This new player has changed the focus of how genes are regulated in the cell.
Previously, the major players in the cell were proteins. They are the functional unit and workers in the cell. For example, the protein called BRCA1 (breast cancer 1 protein) is involved in DNA repair when the DNA is damaged. It is also mutated in some people and that mutation is linked to the development of some forms of breast cancer.
Proteins are made by translation of a RNA molecule, remains in the cell for a defined period of time (depending on the specific protein) and is degraded by other protein-dependent mechanisms of various sorts. The RNA in the cell functioned to translate the code from DNA to the protein. Some specialized RNAs, messenger RNA, transfer RNA and ribosomal RNA, exist to help in this process.
That was prior to the 1990s and the recognition of non-coding RNAs, especially microRNA (aka miRNAs). Non-coding RNAs are RNA molecules that have a role in the cell, but do not create proteins to carry out that function. This includes the RNAs mentioned above (transfer, messenger and ribosomal) and also includes a newly identified class of RNAs that have very important roles in the cell, the small non-coding RNAs. This class now contains microRNAs, small interfering RNAs, and Piwi-associated RNAs. For today, the focus will be microRNAs.
MicroRNAs are short stretches of RNA nucleotides (the A,C,U,G bases) that are only 20-30 bases in length. It’s short (transfer RNAs, messenger RNAs can be 100-1000s of nucleotides long)! These miRNA are very important for controlling protein expression levels and do so by controlling the translation step from messenger RNA to protein. (For example, the BRCA1 gene is encoded in the DNA on Chromosome 17. When it is expressed the DNA is transcribed and a BRCA1 messenger RNA is created. This messenger RNA is then translated by transfer and ribosomal RNA and other proteins into the actual BRCA1 protein).
MicroRNAs control protein expression in a variety of ways - they bind to the messenger RNA and degrade it so there is no RNA template available to create the protein - or they bind to the messenger RNA and prevent the message from being translated into the protein by disrupting the translation machinery without altering the messenger RNA amount itself. In either case, the overall amount of the protein product is reduced and this can have dramatic consequences on the cell.
The real advantage of microRNAs is speed. They can rapidly control the level of protein in a cell, much faster than if a protein has to be made from turning on the transcription of the DNA, then creating the messenger RNA, then creating the protein. Alternatively, it can rapidly remove a protein from a cell by binding to the messenger RNA and essentially silencing it. Need more protein? Remove the microRNA bound to the messenger RNA and more protein will be translated! Have too much and need to eliminate protein quickly? Bind a microRNA to the messenger RNA and prevent protein translation.
This area of research has exploded! Since they were discovered, over 400 different microRNAs have been identified. They control expression of many proteins and are critically important in the cell. Many microRNAs have been shown to be altered in cancers (either too much or too little) suggesting that a problem (and therefore a potential therapeutic target) could be that microRNA expression is out of whack.
This discovery will change how scientists think about control of protein expression. Control of protein expression is no longer a linear process.
Just entering microRNA into the PubMed scientific literature search engine yields almost 8500 papers on the topic already! I think in the future we’ll see use of microRNAs and these other small non-coding RNAs as therapy to treat disease.
Thank you for the topic suggestion!
In the 1990s a new player took the stage in scientific research, microRNAs. This new player has changed the focus of how genes are regulated in the cell.
Previously, the major players in the cell were proteins. They are the functional unit and workers in the cell. For example, the protein called BRCA1 (breast cancer 1 protein) is involved in DNA repair when the DNA is damaged. It is also mutated in some people and that mutation is linked to the development of some forms of breast cancer.
Proteins are made by translation of a RNA molecule, remains in the cell for a defined period of time (depending on the specific protein) and is degraded by other protein-dependent mechanisms of various sorts. The RNA in the cell functioned to translate the code from DNA to the protein. Some specialized RNAs, messenger RNA, transfer RNA and ribosomal RNA, exist to help in this process.
That was prior to the 1990s and the recognition of non-coding RNAs, especially microRNA (aka miRNAs). Non-coding RNAs are RNA molecules that have a role in the cell, but do not create proteins to carry out that function. This includes the RNAs mentioned above (transfer, messenger and ribosomal) and also includes a newly identified class of RNAs that have very important roles in the cell, the small non-coding RNAs. This class now contains microRNAs, small interfering RNAs, and Piwi-associated RNAs. For today, the focus will be microRNAs.
MicroRNAs are short stretches of RNA nucleotides (the A,C,U,G bases) that are only 20-30 bases in length. It’s short (transfer RNAs, messenger RNAs can be 100-1000s of nucleotides long)! These miRNA are very important for controlling protein expression levels and do so by controlling the translation step from messenger RNA to protein. (For example, the BRCA1 gene is encoded in the DNA on Chromosome 17. When it is expressed the DNA is transcribed and a BRCA1 messenger RNA is created. This messenger RNA is then translated by transfer and ribosomal RNA and other proteins into the actual BRCA1 protein).
MicroRNAs control protein expression in a variety of ways - they bind to the messenger RNA and degrade it so there is no RNA template available to create the protein - or they bind to the messenger RNA and prevent the message from being translated into the protein by disrupting the translation machinery without altering the messenger RNA amount itself. In either case, the overall amount of the protein product is reduced and this can have dramatic consequences on the cell.
The real advantage of microRNAs is speed. They can rapidly control the level of protein in a cell, much faster than if a protein has to be made from turning on the transcription of the DNA, then creating the messenger RNA, then creating the protein. Alternatively, it can rapidly remove a protein from a cell by binding to the messenger RNA and essentially silencing it. Need more protein? Remove the microRNA bound to the messenger RNA and more protein will be translated! Have too much and need to eliminate protein quickly? Bind a microRNA to the messenger RNA and prevent protein translation.
This area of research has exploded! Since they were discovered, over 400 different microRNAs have been identified. They control expression of many proteins and are critically important in the cell. Many microRNAs have been shown to be altered in cancers (either too much or too little) suggesting that a problem (and therefore a potential therapeutic target) could be that microRNA expression is out of whack.
This discovery will change how scientists think about control of protein expression. Control of protein expression is no longer a linear process.
Just entering microRNA into the PubMed scientific literature search engine yields almost 8500 papers on the topic already! I think in the future we’ll see use of microRNAs and these other small non-coding RNAs as therapy to treat disease.
Thursday, August 12, 2010
Direct to Consumer genetic testing
There has been a lot of news lately about the accuracy and reliability of direct to consumer (DTC) genetic testing kits. These are relatively inexpensive testing kits that use a sample of your DNA, obtained by scraping the inside of your cheek, to analyze for gene alterations and to determine your genetic predisposition for a disease or other trait like hair color or if you smell that strange smell that asparagus turns your pee! Basically, you send your DNA sample to a company and they tell you your “risk” of developing different diseases over your lifetime. The issue is that these tests are not very reliable. Unfortunately, while the kits themselves are cheap, the profiling can be quite pricey. So, you are paying for data that may be worthless.
A few months ago, the FDA tested these kits. They bought 10 kits from 4 companies and sent 2 samples from each person. One sample had factual data about age, race and gender but the second sample had fictional data supplied to test the accuracy of the findings.
The results of the test were surprising. First, some of the companies failed to disclose before the test was submitted that the African American or Asian samples could not be accurately analyzed. Secondly, the different samples yielded different results. Some samples did not align with current medical conditions, i.e. existence of heart disease. One sample scored below average using one kit for risk of prostate cancer and hypertension but above average on a different kit for the same disease. Why are they different? They should be the same.
These results raise important scientific questions about genetic testing and personalized medicine. Several genes that predict how a patient will respond to a certain therapy have been identified. For example, estrogen receptor alpha and progesterone receptor alpha expression for administration of tamoxifen in breast cancer, expression of certain mutations of BRCA1 or 2 increases the risk for developing breast cancer, expression of K-Ras in colon cancer identifying those likely to respond to cetuximab or panitumumab, expression of EGFR protein predicts use of Iressa, gefitinib or erltinib as a lung cancer therapy. The list goes on. Personalized medicine and the genes known to help predict disease or response to therapy is powerful stuff. It can, and will, really change how patients are tested and treated for disease. It is a young field and changing rapidly as more is being understood, but it isn’t ready for companies like these that provide information on your risk for diseases. The data they provide is incomplete or worse, inconclusive and wrong. The data isn’t reviewed by a healthcare provider and therefore has no medical oversight. Providing such services just muddies the water and prevents real progress in understanding the science of diseases.
There is active debate about regulating these companies with some proposing a complete ban on them for now. Whatever happens, I just hope that this doesn’t keep people from believing in science and the power of the new technologies and insights being realized today.
A few months ago, the FDA tested these kits. They bought 10 kits from 4 companies and sent 2 samples from each person. One sample had factual data about age, race and gender but the second sample had fictional data supplied to test the accuracy of the findings.
The results of the test were surprising. First, some of the companies failed to disclose before the test was submitted that the African American or Asian samples could not be accurately analyzed. Secondly, the different samples yielded different results. Some samples did not align with current medical conditions, i.e. existence of heart disease. One sample scored below average using one kit for risk of prostate cancer and hypertension but above average on a different kit for the same disease. Why are they different? They should be the same.
These results raise important scientific questions about genetic testing and personalized medicine. Several genes that predict how a patient will respond to a certain therapy have been identified. For example, estrogen receptor alpha and progesterone receptor alpha expression for administration of tamoxifen in breast cancer, expression of certain mutations of BRCA1 or 2 increases the risk for developing breast cancer, expression of K-Ras in colon cancer identifying those likely to respond to cetuximab or panitumumab, expression of EGFR protein predicts use of Iressa, gefitinib or erltinib as a lung cancer therapy. The list goes on. Personalized medicine and the genes known to help predict disease or response to therapy is powerful stuff. It can, and will, really change how patients are tested and treated for disease. It is a young field and changing rapidly as more is being understood, but it isn’t ready for companies like these that provide information on your risk for diseases. The data they provide is incomplete or worse, inconclusive and wrong. The data isn’t reviewed by a healthcare provider and therefore has no medical oversight. Providing such services just muddies the water and prevents real progress in understanding the science of diseases.
There is active debate about regulating these companies with some proposing a complete ban on them for now. Whatever happens, I just hope that this doesn’t keep people from believing in science and the power of the new technologies and insights being realized today.
Friday, August 6, 2010
genes, pseudogenes and the increasing complexity of the genome
Research into the human genome has led us to understand that our DNA is very complex. The genes that make us who we are are encoded in our DNA. That is straightforward, right? The research that has taken place since the genome was sequenced 10 years ago has redefined what a gene really is.
In order to have a functional product from the DNA, the gene is transcribed from DNA into messenger RNA (mRNA) and then translated into a protein, the functional element in the cell. The simple (old) definition is that a gene is a made up of several parts, a coding region that holds the sequence for the protein that will carry out the function of that gene, a promoter region that controls how the gene is turned on and off and is usually found just in front of the coding region, and a third region called the 3’ untranslated region (3‘UTR) that controls how long the RNA will exist in the cell. There may be other control elements that determine if or regulate how a gene is expressed including enhancer regions that “enhance” the transcription of the gene in to RNA, but in essence, what constitutes a gene was easily defined. There was “extra” DNA that didn’t encode a gene, however, and this extra sequence was essentially useless. It didn’t have a role and was garbage or filler. It is unimportant.
Now, after 10 years of genomic research, some of the complexity of a gene has been realized. The “unimportant” sections of DNA, in turns out, are important. The definition of a gene isn’t so simple. Besides genes that code for proteins, there are pseudogenes that are the same sequence as genes but work to prevent the activity of the gene. Some genes, depending on where the sequence for them starts and stops, can produce many different proteins that have vastly different functions. These are called alternative stop codons (aka sites) and they can produce longer or shorter genes and lead to dramatically different functions!
Together all this means that there is more regulation of genes than previously thought! Our cells, and bodies for that matter, are extraordinarily complex. Each system has been finely and precisely coordinated to control how it works. This also means that there are new avenues that can be exploited for therapy. Now that new entities have been identified, novel and innovative ways to prevent or increase their function is being investigated. This could lead to a new therapy and hopefully will reduce unwanted side effects.
In order to have a functional product from the DNA, the gene is transcribed from DNA into messenger RNA (mRNA) and then translated into a protein, the functional element in the cell. The simple (old) definition is that a gene is a made up of several parts, a coding region that holds the sequence for the protein that will carry out the function of that gene, a promoter region that controls how the gene is turned on and off and is usually found just in front of the coding region, and a third region called the 3’ untranslated region (3‘UTR) that controls how long the RNA will exist in the cell. There may be other control elements that determine if or regulate how a gene is expressed including enhancer regions that “enhance” the transcription of the gene in to RNA, but in essence, what constitutes a gene was easily defined. There was “extra” DNA that didn’t encode a gene, however, and this extra sequence was essentially useless. It didn’t have a role and was garbage or filler. It is unimportant.
Now, after 10 years of genomic research, some of the complexity of a gene has been realized. The “unimportant” sections of DNA, in turns out, are important. The definition of a gene isn’t so simple. Besides genes that code for proteins, there are pseudogenes that are the same sequence as genes but work to prevent the activity of the gene. Some genes, depending on where the sequence for them starts and stops, can produce many different proteins that have vastly different functions. These are called alternative stop codons (aka sites) and they can produce longer or shorter genes and lead to dramatically different functions!
Together all this means that there is more regulation of genes than previously thought! Our cells, and bodies for that matter, are extraordinarily complex. Each system has been finely and precisely coordinated to control how it works. This also means that there are new avenues that can be exploited for therapy. Now that new entities have been identified, novel and innovative ways to prevent or increase their function is being investigated. This could lead to a new therapy and hopefully will reduce unwanted side effects.
Sunday, August 1, 2010
stem cells as cancer therapy?
One last stem cell related blog and I promise, I’ll move on to a new topic.
There have been some interesting articles in the science literature about the potential use of stem cells to treat cancer. This is based on basic research and is not yet used in any clinical trials or ready for prime time. It is an interesting idea that MAY show promise as a therapy someday but is NOT there yet. Therefore, I am not advocating that it should be sought out as a therapy now or that if this does exist anywhere it will be beneficial. Time will tell as more research is conducted if it is a good therapy or if some other therapy will come of out of this research.
Mesenchymal stem cells are cells found in the bone marrow. Actually, there are two types of bone morrow derived stem cells, hematopoetic (that go on to become white blood cells) and mesenchymal (that can differentiate into many cell types and are involved in wound/tissue repair). It also turns out that mesenchymal stem cells (MSC), because of their role in wound repair and tissue regeneration, migrate to cancer tumor sites. The current understanding is that tumor cells release agents called chemokines that attract MSCs to the site. The role of these MSCs within tumors is still largely unclear but it is thought that they may contribute to supporting tumor growth. Interestingly, scientists have been looking at how to use this migration capacity of MSCs to turn these cells into cells that deliver some form of therapy (aka a vector for cancer therapy). Basically, MSCs can be engineered to express a gene that will kill the tumor cells. For example, MSCs can be made to express the interferon beta protein and then used to target to melanoma tumors. Interferon beta has been shown to inhibit tumor growth by causing cells to stop growing and die.
The advantage of using MSCs instead of just injecting a drug or ingesting a pill is that MSCs could be better at targeting to a tumor site and reducing the unintended side effects by affecting non-tumor cells. This would be especially beneficial for tumors that are hard to access such a solid tumors in the breast, etc...
As I said at the beginning of this piece, this is a test of a theory that is being investigated. It is a very attractive idea, to use cells that preferentially go to tumor sites as a method to deliver therapy. There is still a lot that isn’t known yet, like will the MSCs themselves promote tumor growth? For now, it is a novel way to deliver therapy directly to the tumor site. Hopefully, this research will continue to progress.
There have been some interesting articles in the science literature about the potential use of stem cells to treat cancer. This is based on basic research and is not yet used in any clinical trials or ready for prime time. It is an interesting idea that MAY show promise as a therapy someday but is NOT there yet. Therefore, I am not advocating that it should be sought out as a therapy now or that if this does exist anywhere it will be beneficial. Time will tell as more research is conducted if it is a good therapy or if some other therapy will come of out of this research.
Mesenchymal stem cells are cells found in the bone marrow. Actually, there are two types of bone morrow derived stem cells, hematopoetic (that go on to become white blood cells) and mesenchymal (that can differentiate into many cell types and are involved in wound/tissue repair). It also turns out that mesenchymal stem cells (MSC), because of their role in wound repair and tissue regeneration, migrate to cancer tumor sites. The current understanding is that tumor cells release agents called chemokines that attract MSCs to the site. The role of these MSCs within tumors is still largely unclear but it is thought that they may contribute to supporting tumor growth. Interestingly, scientists have been looking at how to use this migration capacity of MSCs to turn these cells into cells that deliver some form of therapy (aka a vector for cancer therapy). Basically, MSCs can be engineered to express a gene that will kill the tumor cells. For example, MSCs can be made to express the interferon beta protein and then used to target to melanoma tumors. Interferon beta has been shown to inhibit tumor growth by causing cells to stop growing and die.
The advantage of using MSCs instead of just injecting a drug or ingesting a pill is that MSCs could be better at targeting to a tumor site and reducing the unintended side effects by affecting non-tumor cells. This would be especially beneficial for tumors that are hard to access such a solid tumors in the breast, etc...
As I said at the beginning of this piece, this is a test of a theory that is being investigated. It is a very attractive idea, to use cells that preferentially go to tumor sites as a method to deliver therapy. There is still a lot that isn’t known yet, like will the MSCs themselves promote tumor growth? For now, it is a novel way to deliver therapy directly to the tumor site. Hopefully, this research will continue to progress.
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