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Breast cancer is the leading cause of cancer death among women world wide. Like all types of cancer it is notoriously difficult to cure because it is not a simple disease - like a bacterial infection - rather it is a complex failure in cell regulation. This failure results in a single rogue cell that grows aggressively and can become invasive - attacking and destroying surrounding tissues - or metastatic - spreading to other parts of the body. There are a number of steps involved in a benign tumor cell becoming metastatic. First the tumor invades surrounding tissue, then can enter the circulatory system and travel through the body, followed by invasion of a new tissue and then a couple of stages of metastasis. Cancer researchers study each of these steps to determine the biological mechanisms involved the ultimate goal being to find means of arresting the process. What makes cancer such a tricky beast is that cancer cells hijack normal biological processes to do their dirty work.

Research published in this weeks Nature journal from a researchers at the Massachusetts Institute of Technology and Sloan-Kettering Cancer Center describes such a biological hijacking. What makes this work particularly interesting is that it involves a recently discovered type of regulation, which won a Nobel Prize for its discoverers last year. The central dogma of molecular biology states that DNA is transcribed into RNA which is translated into protein, the functional unit of most cellular processes. In the last couple of decades however, scientists have begun to find exceptions to this rule, particularly involving RNA. In addition to its “normal” role as a template for making proteins, RNA can act alone to catalyze a number of cellular processes without being translated to protein. One of the more interesting things that RNA can do is regulate itself. There are species of very small RNAs, known as microRNAs (miRNA), that are used as a means of regulating transcription of DNA or gene expression. These miRNA are very important in normal human growth and development and represent another way in which the expression of genes is regulated.

Previous research has been done comparing the levels of miRNA present in normal versus cancerous cells and some miRNA species were found to be expressed at a much higher level in tumor cells. The MIT researchers focused on one in particular, miR-10b, which was notably upregulated in metastatic breast cancer cells. They then seek to gain an understanding of what this miRNA is doing by transgenically overexpressing it in mammalian cell cultures - in other words they mimic what is happening in cancer cells in a system that they can control. Using this system, the researchers determine that miR-10, when overexpressed, aids the tumor cell in tissue invasion and migration through the circulatory system. These cell culture lines were then implanted into mice and animals carrying the miR-1o overexpressing lines developed invasive tumors in various tissues. The image above is of metastatic secondary tumors in lungs of these mice. This result indicates that miR-10b is capable of triggering invasion and migration in vivo as well as in culture.

The authors also worked out the way in which miR-1ob is regulated. A gene called Twist has been previously identified as important in regulation of metastasis. The reason for this is that it is responsible for the transcription of miR-10b. The gene that miR-10b regulates is known as HOX10D and has been implicated in suppressing tumor cell movement. What is happening in this study is that when Twist is mutated it results in too much of miR-10b being produced. miR-10b normally represses HOX10D to levels required by the cell, when there is too much of miR10-b, there is too little of HOX10D. This is what allows a tumor cell to head toward metastasis.

This work is exciting for a couple of reasons. First it is the first time that miRNA regulation has been implicated in a human cancer. It may be an important breakthrough as 50% of breast cancer patients examined had higher levels of miR-10b in their tumor cells, though they only looked at about 20 patients. There are other miRNAs that are differentially regulated which means that this may be a burgeoning new area of research into cancer mechanisms and one that definitely has been overlooked in the past.

Image Credits:

Woman

Mouse lung tumors

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