Genetic instability in the germline of living organisms has been a common phenomenon since the earliest evolution of eukaryotic cells. According to Darwinian laws of evolution, cells that accrued mutations that conferred them better survival potential were carried on in the germline to create new organisms. However a great increase in genetic instability could lead to loss of viability of cells and therefore the organisms. Especially instability in somatic cells (cells that form specific tissues with the organism) results in the accumulation of mutations that can ultimately fuel cancer (discussed by Weinberg, 2007).
One of the important ways in which normal somatic cells are prevented from undergoing uncontrolled proliferation is by the process of replicative senescence. Chromosomes are capped by specific DNA sequences called “telomeres” that prevent chromosomes from fusing with each other. The telomeres undergo gradual shortening during the lifetime of a cell and the ultimate loss of this protective chromosomal cap causes the cell to undergo crisis resulting in cell death or apoptosis (Stindl 2008). However mutations in cells resulting in loss of the critical apoptotic machinery can cause cells to have random chromosomal fusions after their telomeres are eroded. These cells then accumulate large amounts of genetic instability and can ultimately result in cancer (Cheung, Deng 2008). Telomeric crisis resulting in genetic instability has been stated to be a frequent occurrence in human breast cancer (DePinho, Polyak 2004).
Mouse cells have much longer telomeres than human cells. Because of this mouse cells rarely undergo the “crisis” caused by complete telomere erosion in human cells. Also the much shorter lifespan of mice results in their rarely undergoing complete telomere erosion in a lifetime. So it has been suggested that the mouse genome is more stable than the human genome and does not easily undergo genetic instability (Artandi et al. 2000, Artandi et al. 2002).
Genetic instability is a common feature in human solid tumors (Pihan, Doxsey 2003). The cause for genetic instability is primarily damage of the fundamental genetic material within cells, DNA. DNA damage in cells can occur through multiple mechanisms. Chemically reactive molecules within the cells like reactive oxygen species can affect DNA bases. External agents like chemicals in consumed food products and environmental pollutants can cause slow but significant DNA damage. Radiation in any form can cause major DNA damage if given in large doses (Ayouaz et al. 2008). Besides damage to DNA structure chromosomal instability (CIN) within cells can also be created by alterations (increase or decrease) in their chromosome number, leading to aneuploidy (which means a deviation from the normal or euploid karyotype of a cell). This is caused by the missegregation of chromosomes due to an ineffective mitotic checkpoint control in the M phase of cell cycle. A large contribution to genomic instability and aneuploidy in human cancers is made by double strand break repair defects where damaged DNA is replicated without being repaired.
Several “tumor suppressor” and “caretaker” genes in the eukaryotic genome act as watchdogs and prevent the frequent accumulation of genetic instability. Some of the noteworthy players in this caretaking process are P53 (often referred to as “guardian of the
genome”) and BRCA1 that is an important DNA damage repair protein. P53 acts as a cell cycle checkpoint control protein at both the G1/S and G2/M phases. Cells that lack P53 display an elevated level of genetic instability (Chin et al. 1999, Sharpless et al. 2002). Similarly, BRCA1 functions by forcing cells that have undergone DNA double strand breaks to be repaired by the error-free Homologous Recombination Process (HR). In the absence of
BRCA1 cells are repaired by the error-prone Non Homologous End Joining Process (NHEJ)
that leads to the accumulation of mutations leading to widespread genetic instability and ultimately cancer (Deng 2006). An ongoing debate in the cancer community is whether genetic instability is the cause or the consequence of cancer. It is possible that random mutations resulting in the accumulation of genetic instability sets the stage for cancer progression. Support for this comes from studying early polyps in colorectal cancers that have abundant genetic instability both as aneuploidy as well as microsatellite instability (Bardi et al. 1997, Lengauer, Kinzler & Vogelstein 1997). This suggests that genetic instability may be a process that cancer cells that have undergone mutations acquire to get a growth advantage. However future work is required to find out if this is the case for all cancer types.
Mouse mammary tumor models with loss of p53 alone or combined loss of Rb1 pathway and p53 have been unable to recapitulate the genetic instability seen in human cancers (Liu et al. 2007, Simin et al. 2004). The reason for this could be the more stable genome of the mouse caused by their longer telomeres. To mimic genetic instability seen in human cancers the mouse may require an additional loss of Brca1 resulting in accumulation of unrepaired damaged DNA (Deng 2006). Liu et al., 2007, showed that mouse mammary tumors with loss of both p53 and Brca1 exhibited widespread genomic instability compared
to mammary tumors generated by p53 loss alone. This gave us reason to believe that loss of
Brca1 in addition to the Rb1 pathway inactivation and loss of p53 in mice would lead to
genetic instability and result in mammary gland tumors that better emulate human tumors in numerous aspects. We show here that the loss of Rb1-family, p53 and Brca1 in the mammary gland results in widespread genetic instability along with deletions on chromosome 4 and 10. Significant instability is not observed in mice with loss of Rb1 and
p53 only. This finding further suggests that a weakened genome is more susceptible to the
development of aggressive cancers and genetic instability could be the cause for tumorigenesis.