Multistep carcinogenesis of breast cancer and tumour heterogeneity

Abstract

Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

“…It was reasoned that if the G-allele of SNP309 can accelerate tumorigenesis only in the presence of an active estrogen-signaling pathway, then an earlier age of tumor onset for G/G women versus T/T women should be greatest in the formation of tumors that express high levels of ER (X50%). This is because the percent of tumor cells that stain positive for ER has been shown to correlate with the tumor's dependence on estrogen for growth (Beckmann et al, 1997;Osborne, 1998). Indeed, the G-allele of SNP309 only associated with an earlier age of onset in high ER-positive but not ER-negative IDC formation in two independent patient populations.…”

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

“…More precisely, tumour formation is a result of clonal expansion driven by somatic mutation, developed by a single precursor (monoclonal) that undergoes genetic and biological changes (Khalique et al, 2007;Nowell, 1976). This transformation of normal cells to cancer cells is a multistep process described via the steps of hyperplasia, premalignant change and dysplasia (Beckmann et al, 1997). Cancer cells lose their ability to regulate genome stability which leads to further genetic changes and tumour development (Khalique et al, 2007).…”

Neosis: A Novel Type of Cell Division in Cancer

“…Rapid advances in the current understanding of various oncogenes, tumor suppressor genes, checkpoint controls, genomic instability, and multistep carcinogenesis at the molecular level are the outcome of studies on the mitotic populations of tumor cells (reviewed in refs. [2][3][4][5][6][7][8]. Gene expression profiles obtained from such studies often form the targets for development of novel anti-cancer drugs.…”