Cancer

CANCER; THE SILENT PREDATOR

Cancer is defined as a genetic disorder due to mutations in genes of critical cell proliferation. The hallmarks of cancer include unregulated growth, promotion of differentiation and programmed cell death also known as apoptosis. There are more than 100 types of cancers consisting of many sub-types of tumours in specific organs. The p53 super family of transcription factors consist of several homologues; p73, p53 and p63 which trigger cell apoptosis and cell cycle arrest. Irregularities of the regulatory circuits of normal cells,  hereditary and acquired mutations and other acquired alterations caused by micro and macro-environments in intra and extra-cellular components contribute to the cause of cancer (Hanahan et al 2000). The regulation of cell mechanisms is via the inner building blocks; tumour suppressor genes and oncogenes. These genetic components play an important role in the pathogenesis of cancer that may result in possibilities of future therapeutic interventions using genetic recombinant techniques.

Tumour suppressor genes [TSGs] regulate growth of tumours while oncogenes transform normal cells to carcinogenic status. Mutations in TSGs cause tumour growth. The first TSG identified was BRCA-1 which is commonly observed in breast and ovarian cancers. Other examples of TSGs include BRCA-2, RB-1 and APC. Oncogenes are mostly proto-oncogenes that are formed via mutations in normal cells. Oncogenes cause uncontrollable growth in cells effecting cellular machinery as well as the normal function of the immune system. Examples of oncogenes include KIT, MET and RET. Oncogenes are classified as growth factors [GF], growth factor receptors [GFR], signal transducers [ST], transcription factors [TF] and cell death regulators [CDR] (Fig.1.1c). These classifications are based on the ability to perform functions and their biochemical properties of proteins produced by proto-oncogenes (Gasco et al 2002).

It has been suggested the p53 family which are TSGs provides the most important defence against cancer which activates in response to DNA damage and oncogenic signalling. Cancer related genes essential in embryonic development has revealed mechanisms defining the p53 family’s role in tumorigenesis (IMT, 2009). All members of the family consist of similarities and differences in their regulation and physical and genetic interactions within cells. The members of the family also consist of domains such as the oligomerization domains which are mediators of interactions between multiple splice variant from individual genes (Arrowsmith, 1999). The protein architecture of the family is highly conserved from Drosophila melanogaster to man and consists of a C-terminal oligomerisation [OD], a N-terminal trans-activation domain  [TA] alongside a DNA- binding domain [DBD] which consists of a centrally located DNA sequence. P53 tail consists of a basic domain with the ability to bind sequences of non-specific nucleic acids while both p73 and p63 consist of a sterile α motif [SAM] domain which is implicated in protein-protein interactions. The homology within the DBD is the highest with ≤ 97% of all tumour associated with p53 mutations while both p73 and p63 consists of about 65% amino acid [AA] identities with the DBD of p53. P73, p53 and p63 exhibit various spliced isoforms and consists of a second intronic promoter resulting in ΔN proteins such as ΔNp73, Δ133p53 and ΔNp63. TP73 locus [1p36] is frequently subjected to allele loss in many forms of cancers including neuroblastoma while gene expression studies indicate gene silencing by hypermethylation in inflammatory breast cancers [IBC] and lymphomas (Melino et al 2002).Generation of ΔN is observed via alternative splicing events and initiation of translation such as Δ40P53, Δex2P73, Δex2/3p73 and ΔNp73. The N-terminus is essential for the trans-activation of target genes therefore, isomers such as FLp53, TAp63 and TAp73 which are full length and trans-activated, may be functionally distinguished from ΔN isoforms which are trans-activation compromised, consisting of anti-apoptotic and dominant-negative properties (Stiewe, 2007). 

The mechanism of tumour suppressors is defined by Knusdson’s two-hit hypothesis. The hypothesis was proposed by Alfred Knusdson, a geneticist at the University of Columbia in 1971. The variety of mutations tumour suppressor genes are subjected to results in the loss of function in a recessive manner. Thus, the two-hit hypothesis describes both TSGs must be mutated to produce cancerous cells. The hypothesis was generated for the analysis of the rare Retinoblastoma cancer caused by the Retinoblastoma gene Rb where Knudson had conducted studies between the years 1944-1969 amongst 44 patients. The hypothesis has become the initiating point for current research using tumour suppressors (Chai, 2008). 

A group of family proteins called ASPP which consist of 2 main groups ASPP1 and ASPP2, guide cells away from cell cycle arrest [CCA] and cell death and are regulators of p53 (Slee et al 2003). The ASPP1 and ASPP2 family of proteins are activators of p53 family members via the stimulation of apoptotic activity. Both ASPP1 and ASSP2 induce apoptosis independent of the p53 family. ASPP1 and ASPP2 stimulate the trans-activation of p73 and p63 on promoters such as Bax, PIG3 and PUMA and have been observed in vivo and vitro studies prompting this protein family may suppress tumour growth amongst tumours which express mutant forms of p53 family members. Mutations of p63 and p73 are rare in human cancers (Bergamaschi et al 2004).  Current studies implicate the regions of ASPP that interact with p53  although this is unclear in p63 and p73. Since ASPP1 and ASPP2 are specific activators of p53, wild-type p53 is tolerated in human breast carcinomas through the loss of ASPP activity (Bergamaschi et al 2006). 

Although p53 mutations are common amongst many cancers, p73 over expression is observed in a variety of cancers such as breast cancer [BC] and ovarian cancer [OC]. BC is the most common form of cancer amongst both sexes within the United Kingdom. According to the national statistics tabulated in 2006, there were 45,822 new cases of BC with 45,508 amongst females and 314 in males and the rates of mortality for BC in the UK. It has been established using incidence and mortality data from 2001-2005, the life time risk of the development of BC is 1 in 9 for women. 81% of female BC victims are within the age of 50 and over while 48% of this is within 50-69 age groups. However, the NHS has reportedly extended the BC screening programme for ages between 47-73 from February 2009 and is to be completed by 2012. BC is also the most common form of cancer amongst women under the age of 35 while 1,500 new cases have been reported amongst women between the ages 35-39 in 2009 (Cancer Research UK, 2009). OC is the second most common cause of gynaecological cancer; however has a life time risk of developing the disease of 1 in 50 in women within the UK. There were 6,596 new case of OC in 2006 and their rate of mortality during 2007. OC is predominantly observed within post-menopausal females with 80% cases being diagnosed amongst over 50 year olds, although the highest risks are for women 65 years and above (Cancer Research UK, 2009).

The dissecting of the p53 family members in terms of their structure and function has lead to the some understanding of the mechanisms used by the homologues in the initiation of both breast and ovarian cancer. However, the exact pathway p73 adopts to cause these forms of cancer is yet to be identified. The analysis of the TP73 gene has resulted in the understanding of the negative aspects of the molecule such as its association with p53 as well as the positive side such as its potential to become a biomarker, a therapeutic drug or even a diagnostic tool. Current research also depicts the structural comparisons between p73, p63 and p53 that have lead to the conclusion that although some homology exists, every homologue directs it’s interactions through their variants and isoforms. The structure of p53 is more understood compared to p63 and p73 while the functions attributed to each one of the members are unique. Functions of p73 are more indirect and take a developmental role while both p53 and p63 have a direct role in tumouriogenesis. Thus, further research and con-current experiments involving these proteins may show the activation pathways that may be used strategically to prevent breast and ovarian cancer. This may also implicate strategies that may be used in the management of the conditions and preventative methods against other forms of cancer.