Growth factors and transcription factors

Bhlhb2 a basic helix-loop-helix (bHLH) transcription factor, has been suggested to be involved in the control of proliferation and/or differentiation of several cells including fibroblasts.

Fgf1 , placental growth factor, Hes1, pleiotrophin – see 6.1.3.3.1 angiogenesis

Fgf13 induces growth of fibroblasts FGF-13 induced cell growth of lung fibroblasts and aortic smooth muscle cells but had no effect on dermal vascular endothelial cells (Leung et al.1998). Gata3 is found in oestrogen positive breast cancer cells and normal luminal cells. GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3

variants may contribute to tumourigenesis in ESR1-positive breast tumours.

(Usary et al 2004). Gtf2f2 general transcription factor FII is a homologue of the human transcription factor RAP30 (Kobayashi et al. 1992).

Msg1 (cited2) Msg1 enhances Smad-mediated transcription in a manner dependent on p300/CBP (Yahata et al. 2000). Pouf3f3 (class III POU domain transcription factors, Brn-1 and Brn-2) Brn-1 co-operates with reelin in lamination of the developing mammalian cerebral cortex (McEvilly et al. 2002).

6.1.3.3 Angiogenesis

6.1.3.3.1 Angiogenic factors

Ddah is a gene responsible for angiogenesis and oestrogen dependent (Holden, 2003).

Fgf1, placental growth factor (Pgf) and pleiotrophin (Ptn) are implicated in the stimulation of angiogenesis in human breast cancer (Relf et al. 1997).

Jagged2 and Hes1 belong to the notch pathway, which is involved in many aspects of vascular development, where ligands like jagged and delta interact with notch receptors and stimulate the expression of downstream genes like Hes1 (Iso et al. 2003).

Nrcam an ankyrinG-binding protein is up regulated in endothelial cells (EC) forming tubes in 3D collagen (Aitkenhead et al. 2002).

Syndecan-1 (Sdc-1) is up regulated by ephrinB2/EphB4 and plays a role in inflammatory angiogenesis (Yuan et al. 2004).

6.1.3.3.2 Antiangiogenic factors

Adamts1 inhibits endothelial proliferation and blocks the neovascular response induced by growth factors in vivo. ADAMTS1 binds to VEGF and inhibits VEGFR2. (Iruela- Arispe et al. 2003).Type XVIII collagen (Col18a1) is the precursor of endostatin, which has a potent antiangiogenic effect. (O'Reilly et al.

1997)

6.1.3.4 Apoptosis

Gal7 Homodimeric galectin-7 (p53-induced gene 1, LGalS7) promotes apoptosis (Yang and Liu 2003). Expi (extracellular proteinase inhibitor) The expression of the extracellular proteinase inhibitor gene is induced during the involution of mammary gland, when apoptosis occurs in this tissue. Over expression of Expi accelerated apoptosis of mammary epithelial cells under serum starvation (Jung et al. 2004).

6.1.1.5 Proliferation

CyclinD1 promotes the progression from G1 to S. It binds to cdk4 and phosphorylates Rb 1: (Donnellan and Chetty 1998).

Snk (Plk2) is a physiological centrosomal protein and its kinase activity is likely to be required for centriole duplication near the G1-to-S phase transition.

(Warnke et al. 2004). Cdkn2a acts as an antagonist for cyclinD1 and competes with it for binding of cdk4.

Areg (amphiregulin) is involved in the development and involution of the mammary gland. It is known to be regulated by oestrogen, Ha-ras and is a ligand of EGFR. Via EGFR it is able to up regulate cyclin D1. (Menashi et al. 2003 ) AR increased cyclin D1 mRNA and protein and DNA synthesis activity (Shin et al.

2003).

Lef/tcf target genes are ccnd1 mmp7 M phase: Cdc2, Src and Jub.

Cdc2 is phosphorylated by Src and cyclinB1 and promotes M phase. (Draetta et al 1988) Ajuba (Jub) activates Aurora A in mitotic commitment (Hirota et al.

2003).

Adenosine deaminase (Ada) regulates cellular levels of adenosine and deoxyadenosine and acts as a growth promoter (Laban et al. 2003).

Topoisomerase II (Topo II) The alpha isoform of Topoisomerase II is predominantly localised in proliferative tissue (Kondapi et al. 2004)

6.1.3.6 Invasion

Alcam is expressed on low grade prostate tumour cells (Kristiansen 2003) Alcam is usually restricted to subsets of cells involved in dynamic growth and/or migration, including neural development, branching organ development, hematopoiesis, immune response and tumour progression (Swart 2002). In prostate cancer cells with intact E-cadherin , alpha catenin Alcam staining is on the cell membrane, but cytoplasmatic in defect E-cadherin/alpha catenin (Tomita 2000). Arhv is presumably a member of the Wnt/Jnk pathway and might be able to confer a more malignant phenotype as its related gene wrch1 can induce filopodium formation and stress fibre dissolution (Katoh 2002) C4.4a is found in oestrogen positive breast cancer (Fletcher et al. 2003). C4.4A ligand binding confers a migratory phenotype. It has been detected mainly on metastasising carcinoma cells and proposed to be involved in wound healing. (Paret et al.

2005). Cadherin 1 cadE was found up-regulated in MTLn3-induced carcinomas (Wang et al. 2002). Cystatin M (N,E) reduces cell proliferation and migration, invasion and adhesion to endothelial cells (Shridhar et al. 2004). Ddr1 is involved in tumour invasion remodelling and degradation of the extra cellular matrix (Abdulhussein et al. 2004). Il18 suppresses bone metastasis (Nakata et al.

1999), up in DMBA, PhIP induced rat mammary adenocarcinomas (Kuramoto et al. 2002). Matrix metalloproteinases 3,7,12,13 MMP-3 mRNA was detected in 72 of 77 (93.5%) of mammary carcinomas exclusively in stromal cells within the tumours or in the marginal portion of tumours (Nakopoulou et al. 1999).

UMRCase is the proform of MMP-13 which has been found in stroma of microinvasive breast cancer (Uria et al. 1997, Nielsen et al. 2001). The matrix metalloproteases (MMPs) are a family of related matrix-degrading enzymes that are important in tissue remodelling and repair during development and inflammation. Abnormal expression is associated with various diseases such as tumour invasiveness. MMP -3 and -7 have been found in breast cancer (Garbett et al. 2000). Macrophage metalloelastase (MMP-12) is implicated in the pathology of many diseases such as emphysema, aortic lesions and cancer (Fu et al. 2001).

Osteopontin (Opn) stimulates cell motility and nuclear factor kappaB-mediated secretion of urokinase-type plasminogen activator (uPA) through phosphatidylinositol 3-kinase/Akt signalling pathways in breast cancer cells (Das, et al. 2003) t OPN induces alpha(v)beta(3) integrin-mediated c-Src kinase activity in both highly invasive (MDA-MB-231) and low invasive (MCF-7) breast cancer cells, OPN induces alpha(v)beta(3) integrin/EGFR-mediated ERK1/2 phosphorylation and AP-1 activation. Moreover, dn c-Src also suppressed the OPN-induced phosphatidylinositol (PI) 3-kinase activity in these cells indicating that c-Src acts as master switch in regulating MEK/ERK1/2 and phosphatidylinositol 3-kinase/Akt signalling pathways. OPN induces alpha(v)beta(3) integrin-mediated AP-1 activity and uPA secretion by activating c-Src/EGFR/ERK signalling pathways and further demonstrates a functional molecular link between OPN-induced integrin/c-Src-dependent EGFR phosphorylation and ERK/AP-1-mediated uPA secretion, and all of these ultimately control the motility of breast cancer cells (Das et al. 2004). Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status. (Wang-Rodriguez et al.

2003). Penk-rs stimulates motility (Drell et al. 2003). Sdc1 Syndecan-1 a protein found on cells and in the extracellular matrix, participates in cell proliferation, cell migration and cell-matrix interactions. SDC-1 expression correlates with the maintenance of epithelial morphology and inhibition of invasiveness (Mennerich et al. 2004).