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Breast cancer: Introduction

Article  in  Seminars in Cancer Biology · October 2001

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Sigurdur Ingvarsson
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Breast cancer: introduction

The most frequent cancer type in females in the allow this identification but some of these methods
Western world is breast cancer, with a lifetime risk still need to be standardized for routine clinical
of the order of 1/10. Our understanding of the diagnosis. Detection of micrometastases in breast
molecular events relating to breast cancer biology cancer patients may be an important adjunct for
and pathogenesis has greatly increased over the last staging and therapy. Several reports have shown the
decade. The development of breast cancer involves prognostic relevance of detection of micrometastatic
several types of genes that need to be activated or cells in bone marrow, and in breast cancer it is
inactivated in order to promote malignancy. The an independent prognostic factor in the node-
sequential steps in gene alterations with respect to negative disease. Identification of tumour markers,
tumour progression are not clear, and are far less well chromosome alterations, gene amplifications, gene
understood than what is currently the best example mutations and expression profile in cytokeratin
of tumour progression, that is, colo-rectal carcinoma. positive cells from bone marrow confirms their
Still, the large number of alterations that have been malignant nature and can explain their biological
identified in breast tumours at the genetic level fit behaviour or phenotype. Both in vitro and in vivo
the model of multistep carcinogenesis. Breast cancer models are of importance for better understanding
is sometimes associated with predisposing mutations of the biology of the disseminated tumour cells.
in the germline but is essentially a somatic cell genetic The role of oestrogen in growth, development and
disease. In the present issue of Seminars in Cancer function of the mammary gland is well established,
Biology selected topics on breast cancer biology and and detection of oestrogen receptors (ERs) in
genetics are reviewed. breast tumours has for some time been beneficial,
Putative precursor stages to invasive breast tumour together with progesterone receptors, for prognosis
growth are hyperplasias and cancer in situ. Breast
and selection of cancer therapy. The review by
cancer can also progress further to a metastatic
Stephanie Sommer and Suzanne A. W. Fuqua
disease, where axillary nodes are the most common
focuses on the recent understanding of ER action
sites, but distant metastases can also occur, where
in relation to breast cancer. Some of the new
bone and bone marrow are among the major
discoveries of ER are: a new receptor (ERβ),
locations. Micrometastases in breast cancer patients
new ERα sequence variants (only in a minority
have been studied recently, as reviewed by Klaus
of tumours), co-regulatory proteins modulating
Pantel and Marcus Otte. One way to detect the
ER activity, the importance of conformational
micrometastases is to collect a bone marrow sample
changes of ER, alternative downstream signalling
and score for epithelial characteristics of the cells,
namely expression of cytokeratins by immunocy- pathways, and cross-talks of signal transduction
tochemistry. Such micrometastases are relatively pathways. Patients with ER positive tumours have
frequent in breast cancer (25–43%). Since metastatic better prognosis and these tumours are considered
cells are targets for therapeutics, it is optimal to to be hormone-dependent and can be treated
detect them at a single-cell level and to detect with tamoxifen or by other alternatives that affect
their phenotype and viability. Recent developments oestrogen action. Nonetheless, some of the breast
in immunocytochemical and molecular methods tumours are, or can become, resistant to hormonal
therapy, even in cases where the ER is expressed.
The anti-oestrogen resistance mechanism is not
fully understood but could be explained by some
c
2001Academic Press of the following mechanisms: reduced expression
1044–579X / 01 / 050323+ 04 / $35.00 / 0 of ER in the tumours (methylation of the promoter

323
S. Ingvarsson

may be involved in some cases), the existence tumour cell. The TP53 differs from several other
of sequence variants (higher frequency has been tumour suppressor genes by the high prevalence
reported in metastatic compared to primary tumour of missense mutations. Presumably this gives rise
growth), up-regulation of co-repressors, down- to mutated forms of p53 proteins that can act in
regulation of co-activators or rapid inactivation of a dominant negative manner. As this transcription
the hormone. Mutations in ER can modulate its factor acts as a tetramer, one mutated subunit could
activity by affecting residues that play a major role, be sufficient to affect the function of the protein
including phosphorylation of a co-factor binding complex. In breast cancer 30% of TP53 mutations
site. The model of oestrogen action is not as simple cluster at eight hotspot codons and a similar profile
as formerly believed, partly by the definition of the of TP53 mutations is detected as in other cancer
different protein interacting partners, co-activators types, except that there is a slightly lower frequency
and co-repressors. In some of the non-classical of transversions and slightly higher frequency of
models of ER activation, the AF1 or AF2 mediated ER transitions. The transversions are generally more
regulated expression is dependent on cell types, and common in cancers in which carcinogens play an
ER can enhance the activity of the Sp1 transcriptional important role. The mutation pattern in the TP53
factor through protein–protein interaction. In gene is different in Western countries compared
addition, ligand independent transcriptional with Japan, particularly in individuals diagnosed with
activation by ER can be controlled by serine or breast cancer under 45 years of age, and there are
tyrosine phosphorylation on AF1 or AF2. The ER also reports on higher prevalence of small deletions
action is further complicated by cross-talks with in specific regions of the USA. These differences in
other signal transduction pathways. Some of the anti- the TP53 mutations spectrum support the hypothesis
oestrogens (e.g. tamoxifen) function as antagonists, that a fraction of breast cancer mutations may be
that have oestrogen function in some tissues and anti- induced in response to exposure to environmental
oestrogen in others, i.e. can act as SERMs (selective carcinogens. In all, 196 germline mutations have
ER modulators). The gene for one of the co-activators been detected in the TP53 gene and 164 of them exist
of ER, the SRC3, is located on a chromosome region in cancer families. Breast cancer is the most frequent
20q found to be amplified and with increased protein type of cancer in patients with inherited TP53
expression in a fraction of breast tumours. This mutation, and mutation of one allele can predispose
overexpression might result in enhanced oestrogen- to early disease. The pattern of germline mutations in
induced growth stimulation. Further research on comparison with sporadic mutations show increased
these recent findings on the ER will undoubtedly cast frequency of transitions at CpG sites and reduced
more light on some of the biological behaviour of frequency of transversions at non-CpG sites. This
breast cancer growth in the future. could possibly be explained by a specific endogenous
The most frequent point mutations in breast mutagenic process that acts in the germline. Patients
tumours are in the TP53 tumour suppressor gene. with germline mutation in BRCA1 or BRCA2 genes
But mutations in the TP53 gene occur only in about have a higher mutation rate in the TP53 gene and
30% of breast tumours, that is considerably less codon 163 is a hotspot. In these tumours there
than the average 50% documented for all tumour is a higher frequency of mutations at AT and a
types. Magali Olivier and Pierre Hainaut review lower frequency of GC mutations at non-CpG sites
the 1392 TP53 mutations in breast cancer so far in tumours with germline mutation in BRCA1 or
described. Several reports show that TP53 mutations BRCA2 genes, compared with sporadic tumours.
are associated with poorer prognosis but it is not as Presumably this reflects the lack of a certain type of
clear whether these tumours have reduced response DNA repair in these tumours. Also, there could be
to therapy. The p53 protein accumulates in over 50% a growth advantage of BRCA1 and BRCA2 mutated
of breast cancer, partly due to the more stable nature tumours upon deactivation of the p53 pathway,
of some of the mutated forms and also because the including escape from the apoptosis programme,
p53 pathway can be activated in tumour cells, by normally turned on by a lack of DNA repair.
stabilization of the w.t. p53 protein. The negative reg- The only gene that is expressed at a constitutive
ulator of p53, the Mdm2 protein, which can promote fragile site, and so far analysed with respect to
p53 degradation, is found overexpressed in a fraction tumour pathogenesis, is the FHIT gene. Recent
of breast cancers, and is presumably an additional findings on the FHIT alterations in breast cancer
mechanism that can turn off the p53 function in the are reviewed by Sigurdur Ingvarsson. Even though

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 Breast cancer: introduction

classical point mutations of the FHIT gene are possible explanation is that there are factors shared
not found in breast cancer, relatively high levels by mutation carriers within a family which modify
of abnormalities are detected, including deletions, their risk. These familial modifiers could be different
methylation and altered or reduced expression. The genetic variants of BRCA1 or BRCA2, or other genes,
relevance of these alterations of FHIT for breast or environmental or lifestyle factors.
cancer pathogenesis is not clear. This high frequency Information on the Brca1 and Brca2 proteins
of alterations could merely reflect the unstable nature has been rapidly increasing over recent years,
of the fragile site in the breast tumour cell, but it mainly with respect to protein–protein interaction
is also possible that FHIT plays a tumour suppressor and their role in transcription, DNA repair and
role. The evidence from cell and mouse models for genome integrity. Furthermore, expression of Brca1
the role of FHIT as a tumour suppressor has recently and Brca2 and phosphorylation of the Brca1 is
been increasing dramatically. regulated during the cell cycle. Despite several
John L. Hopper writes a critical review on similarities affecting these cell functions, the Brca1
hereditary breast cancer, mainly focussing on and Brca2 proteins are unrelated with respect to
BRCA1 and BRCA2, but BRCAX, ATM and TP53 amino acid sequence. As Åzke Borg reviews, the
are also addressed. In general it is widely accepted Brca proteins are part of multiprotein complexes.
that germline mutations in BRCA1 or BRCA2 The Brca1 protein is part of the BASC (Brca1
considerably increase the lifetime risk of developing associated genome surveillance complex) that
breast cancer. It was a major breakthrough in the includes other DNA repair proteins and some of the
breast cancer field when the BRCA1 and BRCA2 complexes detected also include proteins involved
were cloned. Until then, it was known that breast in transcription, protein degradation and mitotic
cancer was partly familial and some of the families checkpoints. All this interaction suggests that the
showed linkage to chromosomes 17q and 13q. After Brca1 protein (and Brca2) has an essential function
the discovery of the BRCA1 and BRCA2, the first in multiple biological pathways. Borg also reviews
material to be screened for mutations was from the histological and chromosomal characteristics
high-risk multicancer families. This work lead to the of breast tumours in individuals carrying BRCA1
conclusion that there was relatively high penetrance or BRCA2 mutations. Tumours arising in carriers
of breast cancer when one of these genes was mutated of BRCA1 mutation differ morphologically and
in germline. Today, several population-based studies immunohistochemically from those caused by
show that the penetrance may be much lower than BRCA2 mutations and also from sporadic cases.
originally estimated. There can be a great variation Compared with sporadic tumours, the BRCA1
in risk, and not all mutations appear to confer a high and BRCA2 tumours have higher overall grade,
risk in all settings. This variance in penetrance is higher mitotic activity, lower frequency of lobular
detected for different genes and different mutations breast cancer, higher frequency of non-infiltrative
within the particular gene. Therefore it is difficult to and smooth edges (continous pushing margins),
generalize, and there is uncertainty about the cancer and lower frequency of tubule formation/tubular
risk in mutation carriers. The risk estimate associated tumours. In addition BRCA1 tumours have lower
with a mutation depends not only on its type and frequency of cibriform cancers and ductal carcinoma
location, but also on the sampling frame of the study in situ. Atypical lymphocyte infiltration is also
from which that estimate was derived. In Hopper’s detected in BRCA1 tumours, and may be due to the
review the putative modifications (genetic, epigenetic presence of specific antigens. In general tumours
and environmental) of cancer risks in mutation car- with BRCA2 mutations are more heterogeneous
riers are discussed. Since breast cancer is a common with respect to phenotype than BRCA1 mutated
disease, small familial clusters could occur by chance tumours. Chromosome abnormalities are also of
alone. This means that cases believed to be hereditary higher frequency, as demostrated by pleomorphism
may be sporadic. A large number of BRCA1 or BRCA2 and aneuploidy of BRCA1 tumours, and several
carriers do not appear to have a family history of chromosome abnormalities detected in BRCA1 and
breast cancer, nor are they members in a multiple- BRCA2 tumours. These chromosome abnormalities
case family. This proportion is presumably higher are of higher frequency in hereditary than in sporadic
in families with a low number of individuals in tumours, and a particular pattern is detected that
each generation, and where modifying factors are distinguishes BRCA1 from BRCA2 tumours, as
favourable for suppression of tumour growth. One well as both of these tumour types from sporadic

325
S. Ingvarsson

tumours. This phenotype of the genome in BRCA1 much to our understanding of the roles of these
and BRCA2 tumors is compatible with the normal genes in mammary tumour initiation, promotion
role of these genes in the maintenance of genomic and progression. Loss of Brca1 function does not
stability. The general aggressive appearance could directly initiate tumourigenesis, but promotes
be related to intrinsic chromosomal instability, genetic instability, triggering further alterations that
defective DNA repair and centrosome regulation. are critical for tumour formation, such as in tumour
Particular expression profiling is detected in BRCA1 suppressor genes (TP53) and oncogenes, ultimately
and BRCA2 tumours (see also the last review in leading to tumour formation (see, also, the review
this issue). Thus histology, chromosome alterations by Oliver and Hainaut on the TP53 gene). This
and expression profiling can distinguish between process of mutation accumulation requires time and
sporadic, BRCA1 and BRCA2 breast tumours, may account for the latency of cancer incidence in
and this information could be relevant for the germline mutation carriers and the rare incidence of
management of breast cancer. somatic BRCA1 or BRCA2 mutations. This tumour
Important information on the function of the progression may start with increased apoptosis that is
BRCA1 and BRCA2 genes and proteins has been defeated at later stages by further gene alterations.
obtained from mouse knockouts, as reviewed by Chu- Microarray (cDNA, CGH and tissue) studies in
Xia Deng and Steven G. Brodie. APC, ATM, PTEN breast cancer are reviewed by Outi Monni, Elizabeth
and TP53 knockout mice are also reviewed, including Hyman, Spyro Mousses, Anne Kallioniemi and Olli-P.
the recent studies showing that APC mutation may Kallioniemi. The combined use of these methods
be more relevant to mammary tumourigenesis than allows integration of the cytogenetic and functional
previously believed. Also, a certain mouse strain with views of the cancer genome, which facilitates the
heterozyous p53 knockout may serve as a unique understanding of the molecular basis of breast
model to study breast cancer in the Li-Fraumeni cancer development. Data are now available on
syndrome. One of the advantages of these knockout the expression of a large number of genes from
mice in studying tumour pathogenesis is that mice the overall genome or particular chromosome
with different mutations can be interbred to access regions of interest, i.e. for identification of targets
potential interaction between genes. Some of the of chromosomal changes in breast tumours. Based
findings based on the knockout mice include on gene expression profiles, sporadic breast cancer
activation of the p53 pathway in response to genome can be divided into two major groups of basal
alterations due to BRCA1 or BRCA2 mutations. and luminal types. These studies include the
Several functional aspects of the Brca1 and Brca2 demonstration that ER negative clusters have
proteins have also been clarified in these studies; a subset of basal-like rather than luminal-like
including their role in DNA repair, transcription, tumours, suggesting different tumour behaviour and
apoptosis and cell cycle progression; in general prognosis. Comparison of breast cancer in BRCA1
showing their importance for genome integrity. and BRCA2 mutant carriers, with each other and with
Some of these findings are based on mouse embryo sporadic breast tumours, shows that gene expression
fibroblasts, since the double knockouts are lethal at profiles are distinct in these three subgroups. The
the embryonic stage. But hypomorphic mutations difference in expression includes down-regulation
of Brca2, where the mice survive embryogenesis of ER and certain cytokeratins in BRCA1 tumours
and develop tumours, and conditional knockouts, and up-regulation of cyclinD in BRCA2 tumours.
where one copy of the Brca1 gene is inactive in Gene expression profiles of the individual tumour
germline and the other copy is conditional (spatially samples could possibly be used to accurately predict
and temporally) for the mammary tissue, using the which genetic mutation they carried. These recent
Cre-loxP system, have also been described. These methodological developments have the potential to
conditional knockout experiments have provided have a large impact on breast cancer research, where
direct genetic evidence that p53 loss accelerates they could contribute to improving the specificity
mammary tumour formation in association with of tumour classification, that will eventually be
Brca1 mutation. Loss of Brca1 or Brca2 in the developed into a useful tool for oncologists and
knockout mouse models has shown that this results in lead to the identification of new therapeutic agents.
genome instability and tumour growth, where higher However, some significant questions concerning the
prevalence of mammary tumours is detected in the design, data interpretation and clinical utility of gene-
conditional knockouts. These studies have added expression profile studies remain to be answered.
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