Growth factors and oncogenes in breast cancer

The growth of normal breast epithelial cells is regulated by a complex interacting system of polypeptide factors and by steroid hormones. The cells respond to these factors through receptors which generate mitogenic and other intracellular signals. These second messengers provoke complex responses which may ultimately result in DNA replication and cell division.A comparison of normal cells and tumour cells, either in culture or from primary tumour biopsies, has revealed differences in growth factor and growth factor receptor expression. Such changes may represent aspects of the process of malignant transformation. In addition some evidence suggests that changes in second messenger systems may also occur. Finally several changes in nuclear oncogenes have been observed in breast cancers.It has been proposed that changes in the nuclear oncogenes, perhaps involving the loss of function of tumour suppressor genes, may allow cells to enter the cell cycle. Changes in growth factors, their receptors or intracellular second messenger systems may stimulate unregulated growth. The combination of these events provide a model for the process of carcinogenesis.     

Growth factors and receptors in cancer.

There have been a number of recent developments in mechanisms of action of growth factors and their receptors with particular relevance to cancer. The tyrosine kinase receptor family, in particular, has been shown to be important in tumour growth. These receptors are the products of oncogenes, or can interact with other oncogene pathways. Thus, antibodies to either the receptor or its ligand can be used as therapeutic agents. Peptide analogues of ligands that can block receptor activation are also potential therapeutic agents.     

Growth factor receptors in amyotrophic lateral sclerosis

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing¹²⁵I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.     

Characterization of pp85, a target of oncogenes and growth factor receptors.

An 85,000-molecular-weight polypeptide (85K polypeptide) has previously been identified as a common substrate for tyrosine phosphorylation upon polyomavirus middle T transformation or upon platelet-derived growth factor stimulation of 3T3 cells. In each case, pp85 has an associated phosphatidylinositol kinase activity. The tissue distribution of pp85 was determined by middle T blotting experiments; the highest levels were found in brain, lung, and spleen tissues. High-resolution examination of 85K by isoelectric focusing demonstrated that there are at least 10 different forms. These were resolved into two families, 85K and 86K; the ratio of the two families changed in different cells. Similar forms were found for pp85 associated with pp60v-src. Individual species within each family differed by phosphorylation. Analysis of pp85 and pp86 by immunoprecipitation with anti-phosphotyrosine antibody showed increasing phosphorylation in response to middle T or pp60v-src transformation. The association of middle T with pp85 and pp60c-src was examined in pulse-chase experiments. Association of middle T with pp60c-src was slow and was accompanied by progressive modification of middle T. pp85 formed a dissociable complex with middle T within 2.5 min.     

Cellular oncogenes and cancer

Human oncogenes have been identified either by the ability of normal or tumor DNAs to induce transformation of cells in culture or as the targets of chromosome translocations or DNA amplification in neoplasms. By the combination of these approaches, approximately 40 different genes have been implicated as potential contributors to the development of human neoplasms. The proteins which are encoded by these potential human oncogenes include plasma membrane proteins with tyrosine kinase activity, plasma membrane guanine nucleotide binding proteins, cytoplasmic proteins with serine/threonine kinase activity and nuclear proteins. In many tumors, more than 1 potential oncogene has been activated, suggesting that multiple genes may contribute to neoplasm pathogenesis. I will discuss the identification of these genes, their modes of activation, the diversity of their protein products and their potential roles in both neoplastic and normal cells.     

Growth factors, receptors and cancer

It now appears that the molecular events associated with the mitogenic action of growth factors are also the events perturbed in neoplastic lesions. This review outlines the relevance of our recent progress in the biochemistry of growth factors and their receptors to the induction and maintenance of the neoplastic state.     

Adrenocorticotropic hormone and growth factor receptors in breast cancer

Tissues from 100 cases of breast cancer were analysed immunohistochemically for the presence of adrenocorticotropic hormone (ACTH) or ACTH-like peptides and expression of c-erbB-2 oncoprotein, epidermal growth factor receptor (EGF-R) as well as oestrogen receptor (ER). Immunopositivity for ACTH was found in 15% cases of infiltrating duct carcinoma of the breast, whereas 38% and 36% breast tumours were positive for c-erbB-2 and EGF-R respectively. While 27% cases were positive for ER. The immunoexpressions of all parameters were higher in breast cancer cases with upper age group (45 years or above) than the patients below 45 years of age. A significant correlation was observed between the tumour grade and the expression of c-erbB-2 oncoprotein. Further, a positive association between the immunoexpression of c-erbB-2 and EGF-R was noticed. Interestingly, a statistically significant relationship was found between the immunopositivity of ACTH and ER. The study reflects a probable association of ACTH or ACTH-like peptides in pathological process of breast cancer.     

Growth factor receptors in helminth parasites: signalling and host-parasite relationships

Parasitic helminths remain major pathogens of both humans and animals throughout the world. The success of helminth infections depends on the capacity of the parasite to counteract host immune responses but also to exploit host-derived signal molecules for its development. Recent progress has been made in the characterization of growth factor receptors of various nematode and flatworm parasites with the demonstration that transforming growth factor beta (TGF-beta), epidermal growth factor (EGF) and insulin receptor signalling pathways are conserved in helminth parasites and potentially implicated in the host-parasite molecular dialogue and parasite development.     

Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells

Background  

Somatostatin receptor (SSTR) expression is positively correlated with tumor size and inversely correlated with epidermal growth factor receptor (ErbB) levels and tumor differentiation. In the present study, we compared SSTR1-5 and ErbB1-4 mRNA and protein expression in two breast cancer cell lines: MCF-7 (ER+) and MDA-MB-231 (ERα-).     

Targeting mutant fibroblast growth factor receptors in cancer

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.     

Growth factors, oncogenes, and multistage carcinogenesis

This paper presents evidence that the full repertoire of cellular genes involved in the carcinogenic process is several times larger than that of the known list of proto-oncogenes. Furthermore, this repertoire includes genes whose normal function is related to growth stimulation, as well as genes whose normal function is to inhibit growth or induce terminal differentiation. Multistage carcinogenesis probably results from a complex series of changes in both categories of genes. Despite this complexity, carcinogenesis can be conceived in terms of disturbances in biochemical functions that normally control the expression or function of growth factors, receptors, and pathways of signal transduction. Several protein kinases play a central role in the process of signal transduction. Our laboratory has recently isolated cDNA clones for the enzyme protein kinase C (PKC). These clones should be useful for clarifying the role of PKC in growth control and tumor promotion. Finally, the existence of genes whose normal function is to inhibit cell growth provides a rationale for new strategies of cancer prevention and treatment.