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As you might have seen, I’ve been asking Faculty Members and authors of evaluated papers to say a little about their current research to camera. Recently, Quinn Mitrovich has been talking about intron loss, for example.

In November, Charles Streuli added an evaluation to one from Kamila Naxerova and Isaac Kohane. The paper, Reprogramming human cancer cells in the mouse mammary gland (free link), came from the lab of Gil Smith, a research biologist and Head of Mammary Stem Cell Biology at the National Cancer Institute in Bethesda, MD. Gil kindly agreed to tell us about his current and previous work, so here he is, in his own words:

Gil Smith

I have been a research scientist here in the intramural research program for over 45 years. I came here directly from Brown University where I received a Ph.D. in Biology in 1965. My lifetime research interest is to discover the underlying causes for cancer in the mammalian mammary gland.

Initially, I was drawn to the study of viruses that cause cancer in animals and plants. I began to study the mouse mammary tumor virus (MMTV), which is a RNA beta retrovirus and the causative agent for mammary cancer in MMTV infection-susceptible female mice. MMTV is present in the wild mouse population and causes mammary cancer in these mice. MMTV infection does not kill the infected cell and it is commonly passed to the offspring through the mother’s milk but sometimes, in certain inbred mouse strains, as a proviral gene in germ line DNA.

It became clear to me during my studies that the virus replicated in other cell types in the mouse, but these were not transformed to produce cancers. MMTV must insert a copy of its genome as DNA into the host somatic DNA in order to establish a vegetative life cycle. Over the years it became clear that this event was random and that this activity was essential in the neoplastic transformation of mammary epithelium. It became known as insertional mutation. Since this activity is random in the infected cell genome, it was clear that only certain insertional events could be responsible for neoplastic transformation and in addition expansion of cells containing these inserted proviral copies must represent premalignant and malignant mammary epithelial populations. Thus proviral insertions that were found to activate or otherwise deregulate particular genes commonly in mouse mammary hyperplasia and mammary tumors must identify genes important in transformation of mammary epithelium. These became known as common insertion site (CIS) genes.

In collaboration with Dr Robert Callahan we have identified over 40 genes that fit this category in mouse mammary premalignant and malignant populations. The human homologues of nearly half of these CIS genes are deregulated in human breast cancer. There is a public web site describing these findings. But this is only part of the story. As mentioned above, MMTV transforms mammary epithelium almost exclusively. Therefore there must be some important feature of mammary epithelial biology that promotes this susceptibility. My studies over the last two decades have been focused on this issue.

Mammary epithelial stem cell activity has been demonstrated for over 50 years by tissue transplantation. I proposed roughly 22 years ago that mammary epithelial stem cells existed in mammalian mammary tissue and that they could be characterized by an undifferentiated cellular morphology by electron microscopy. This idea was not initially accepted. Today, however, stem cells are the sine qua non of both regenerative and cancer biology.

My recent studies have sought to demonstrate that a hierarchy of stem cell function exists in the mammalian mammary epithelium and further to show that these activities are dependent upon signals and influences predicated by the tissue microenvironment, which is comprised not only of the stroma and external factors but also the differentiated epithelial cells resident in the organ. To illustrate this, our laboratory has demonstrated that non-mammary cells and cancer cells can contribute normal functioning progeny to regenerating mouse mammary epithelium when mixed with differentiated mammary epithelial cells and placed within the mammary fat pad. Indeed, our recent paper reviewed by the Faculty of 1000 shows that human cancer cells may be reprogrammed in this way as well. The long term goal of these studies is to discern these “reprogramming” signals with the goal of developing a new paradigm for treatment and control of cancer cells in situ.