Current Genomics - Volume 3, Issue 5, 2002

Breast cancer is one of the most common malignancies affecting women; thus, much effort has been put into understanding the genetics of predisposition to breast cancer as well as identifying factors involved in tumor progression and cancer prognosis. Conventional genetics was used to map and clone the two breast / ovarian cancer predisposition genes, BRCA1 and BRCA2. However, the vast majority of breast cancer cases are of a sporadic nature, likely due to a combination of environmental and genetic factors. Other genes have been identified via the analysis of protein interactions, screens based on inverse genomics, yeast two-hybrid assays, far Westerns, GST-pull downs and chromatography / mass spectrometry have been used to identify a number of proteins that interact with BRCA1 or BRCA2. Biological characteristics such as expression levels, protein stability and phosphorylation as well as the biological roles of the BRCA proteins in DNA repair and transcription have also led to the identification of other proteins involved in breast cancer. Recent advances in microarray analysis have allowed the identification of further genetic factors by comparing the transcription profiles of cell lines with varying levels of BRCA1 expression or drug resistance and tumors from patientswith or without BRCA1 / 2 mutations or with different pathobiological types of tumors or prognoses. Additionally, microarray analysis at the DNA level allows for the identification of genes that have been amplified or deleted during cancer progression, and tumor tissue arrays can be used to analyze hundreds of samples simultaneously for the expression of previously identified genetic factors.

The signal transducer and activator of transcription (STAT) proteins and their mechanisms of signaling were originally discovered in the context of normal interferon signaling, where they have been shown to have specific roles in mediating host defenses. It is now known that many cytokines, hormones and growth factors utilize STAT signaling pathways to control a remarkable variety of biological responses, including development, differentiation, cell proliferation, and survival. Given the critical roles of STAT proteins in these fundamental cellular processes, which are often altered in cancer, there is accumulating evidence defining a critical role for STAT proteins in oncogenesis. Members of this relatively small family of proteins serve as both transducers of cytoplasmic signals and nuclear transcription factors, thereby directly converting a stimulus at the cell surface to an alteration in the genetic program. Moreover, STAT proteins can cross-talk with other central signaling pathways, such as the mitogen-activated protein kinase (MAPK) family of proteins and the nuclear receptor signaling pathways. On the other hand, other proteins are known to interact with and modulate STAT signaling pathways, including histone acetyl-transferases and the protein inhibitor of activated STAT (PIAS) family of protein. The present review will try to address some questions concerning the increasingly complex biological functions of STAT proteins, the many diverse mechanisms of STAT regulation and the expanding number of target genes that mediate the biological responses elicited by STAT signaling pathways.

Cancer arises as the result of sequential alterations in growth-controlling genes. Epigenetic factors, such as angiogenesis and surrounding micro-environment can also affect cancer initiation and progression. Tumorigenesis is accompanied by important changes in gene expression in the tumor cell as compared to its normal counterpart. The advent of powerful new techniques such as microarray technology and SAGE has allowed the study of gene expression in neoplastic cells at a scale never before accomplished. Indeed, it is now possible to efficiently measure the levels of thousands of genes expressed in normal and tumor tissues. This global knowledge of gene expression allows the identification of differentially expressed genes and, in principle, the understanding of the complex molecular circuitry regulating normal and neoplastic growth. Such studies have led to molecular profiling of tumors, which have suggested general methods for distinguishing tumors of various biological behaviors (molecular classification), elucidating pathways relevant to the tumorigenesis process, and identifying targets for the detection (biomarkers) and mechanism-based therapy of cancer. The next challenge will be the implementation of these breakthroughs in the clinic, as well as the extension of these paradigms to the fields of proteomics and physiomics.

Normal cellular growth control reflects a carefully orchestrated series of signal transduction events that culminate in changes in gene expression. The proliferative response, in multicellular organisms, is initiated by environmental cues, contributed largely by growth factors, and adhesive influences, provided by the extracellular matrix (ECM). The integrin family of heterodimeric receptors mediates adhesion of cells to the ECM. Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures, termed focal adhesions, which link the ECM to the cytoplasmic actin cytoskeleton. In addition to providing a structural link between the cell and its underlying matrix, focal adhesions contain protein tyrosine kinases, which become activated as a result of cell interaction with the substrate and initiate adhesion-dependent signal transduction cascades culminating in changes in gene expression. In this review, I will consider the role of integrin-mediated signal transduction in regulating genetic changes necessary for controlled cellular proliferation.

The resistance to growth inhibition commonly observed in a variety of TGFβ disabled human cancers, the potential role of TGFβ in the exacerbation of malignancy and the effects of TGFβ in suppressing the immune system, all emphasize the importance of pathways mediated by this polypeptide to the neoplastic process. Early investigations to understand the molecular basis of cancer due to defects in TGFβ signaling were concentrated on examining the abundance of biologically active TGFβ and its binding to TGFβ receptors. However, major breakthroughs in understanding the molecular basis of the TGFβ mediated effects in cancer came from genetic evidence for inactivation of the various players in its signaling cascade. The vast majority of current evidence is derived from the identification of mutations causing structural defects in TGFβ receptors and Smad genes, the downstream effectors of the TGFβ signaling pathway that have emerged from the analysis of human cancers. The involvement of Smads at the receptor level upon activation by a TGFβ bound receptor, their participation in signal transmission to the nucleus and their direct roles in the regulation of target genes have made the various Smad genes critical targets for inactivation of TGFβ signaling in cancer. To date, eight human homologues of the Smad genes have been identified and are classified into three distinct classes based on their structure and function. In this review, we discuss TGFβ signaling via the Smads and the known and predicted points at which TGFβ signaling could become altered in human cancer.

Breast cancers are highly variable with regard to pathological and clinical features. While various different cancers being at different stages of tumor progression might explain some of this variability, we must also consider evidence that breast cancers can also develop along different molecular pathways. This manuscript discusses the extensive heterogeneity of breast cancer at the pathological and molecular level, reviewing evidence for a breast cancer progression model as well as evidence that breast cancer is not a single disease. In addition to this heterogeneity among different breast cancers, there is often pathological and molecular heterogeneity among different areas within individual neoplasms. This heterogeneity within cancers probably reflects genetic instability, and could also explain the ability of breast cancers to adapt to new environmental situations. Understanding this heterogeneity, among different breast cancers as well as within individual cancers, is important for understanding the complexity of this disease and ultimately for managing breast cancer effectively.