Using
Genomic Data to Gain Biological Understanding of Human
Recent Advances in the Identification of Genetic and Biochemical Components of Breast Cancer Predisposition Pp. 389-412
M.K. Sauer
STAT Signaling and Cell Function Pp. 413-423
Fernando de Miguel and Allen
C. Gao
Functional Genomics Approaches in Cancer Research Pp. 425-436
Patrice J. Morin
Gene Regulation by Adhesion-dependent Signal Transduction Pathways Pp. 437-448
Jill K. Slack
TGFb and its Smad Connection to Cancer Pp. 449-476
S. Thiagalingam, K-h. Cheng,
R.L. Foy, H.J. Lee, D. Chinnappan and J.F. Ponte
Heterogeneity in the Pathology and Molecular Biology of Breast Cancer Pp. 477-488
Edward Gabrielson and Pedram
Argani
[Back to top] Recent Advances in the Identification of Genetic and Biochemical Components of Breast Cancer Predisposition
M.K. Sauer
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 patients
with 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.
[Back to top] STAT Signaling and Cell Function
Fernando de Miguel and Allen C. Gao
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.
[Back to top] Functional Genomics Approaches in Cancer Research
Patrice J. Morin
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.
[Back to top] Gene Regulation by Adhesion-dependent Signal Transduction Pathways
Jill K. Slack
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.
[Back to top] TGFb and its Smad Connection to Cancer
S. Thiagalingam, K-h. Cheng, R.L.
Foy, H.J. Lee, D. Chinnappan and J.F. Ponte
The resistance to growth inhibition commonly observed in a
variety of TGFb disabled human cancers,
the potential role of TGFb in the
exacerbation of malignancy and the effects of TGFb
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 TGFb signaling were concentrated on examining
the abundance of biologically active TGFb
and its binding to TGFb receptors.
However, major breakthroughs in understanding the molecular basis of the TGFb 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 TGFb receptors and Smad genes, the downstream
effectors of the TGFb signaling pathway
that have emerged from the analysis of human cancers. The involvement of Smads
at the receptor level upon activation by a TGFb
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 TGFb
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 TGFb signaling via the Smads and the known and
predicted points at which TGFb
signaling could become altered in human cancer.
[Back to top] Heterogeneity in the Pathology and Molecular Biology of Breast Cancer
Edward Gabrielson and Pedram
Argani
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.