Download BRCA1 and BRCA2

Chapter 2
Hereditary Breast Cancer: An Update
on Genotype and Phenotype
Marc Lacroix, and Guy Leclercq
Laboratoire Jean-Claude Heuson de Cancérologie Mammaire,
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Abstract
A significant minority (5-10%) of breast carcinomas is considered of hereditary origin.
Part of them is associated to mutations in the BRCA1 and BRCA2 susceptibility genes,
which have been extensively studied. For their part, tumours in the non-BRCA1/BRCA2
breast cancer (BRCAx) families are increasingly believed to originate from multiple
genetic events, as no “BRCA3” gene has been identified. The existence of specific
“portraits” among hereditary breast carcinomas (HBC) has been questioned. Phenotype
studies have shown that most BRCA1 tumours are part of a “basal epithelial-like” group
of lesions. In contrast, BRCA2 and BRCAx HBC are more heterogeneous, as also
observed with sporadic carcinomas. Genetic analysis has also been applied to HBC,
notably with the objective of resolving the heterogeneity of BRCAx lesions. This chapter
aims to summarise recent data on BRCA1, BRCA2, and BRCAx HBC, and to provide
hypotheses on the origin of BRCA1 lesions, their high frequency of P53 mutations, and
their paradoxical relations to oestrogen-sensitivity.
Introduction
One of the most significant risk factors for the development of breast cancer is a family
history of the disease. 5-10% of all breast carcinomas are clearly inherited, the remaining
cases being considered as “sporadic”. It has been estimated that mutated BRCA1 and BRCA2

Address for correspondence: Marc Lacroix. Laboratoire Jean-Claude Heuson de Cancérologie Mammaire, Institut
Jules Bordet, Université Libre de Bruxelles, 127 boulevard de Waterloo B-1000 Bruxelles,
Belgium,Telephone: ++ 32 2 5413744; Fax: ++ 32 2 5413498; E-mail: [email protected]
2
Marc Lacroix and Guy Leclercq
genes account for autosomal dominant transmission of susceptibility in a majority (70-80%)
of families with hereditary breast-ovarian (BRCA1/BRCA2) or male breast cancers (BRCA2).
However, these estimates might be too high owing to the way patients have been selected,
namely on the basis of a pronounced family history of the disease. On the other hand,
searches for a “BRCA3” gene that would account for the non-BRCA1/BRCA2 (BRCAx)
breast cancer families have been unsuccessful as yet.
Both BRCA1 and BRCA2 are very long genes that may be altered by hundreds of
different and often unique mutations. To avoid a fastidious and costly sequencing of BRCA1
and BRCA2, it was previously hypothesised that tumours associated to mutations in these
genes might be identified through their expression of a specific “portrait”. According to this,
phenotype and genotype analysis of HBC (including BRCAx) have been performed by
various investigators. At the same time, the introduction of tools supporting the massive
analysis of proteins or genes in cancer samples (tissue and DNA micro-arrays) has evidenced
the existence of only a few classes among unselected populations of breast tumours. One of
these, the “basal epithelial-like” class appears to be over-represented in the population of
BRCA1 tumours, which raises interesting questions on the genesis of these lesions. BRCA2
and BRCAx tumours constitute more heterogeneous groups, with a phenotype distribution
very close to that observed in sporadic breast cancers.
BRCA1 and BRCA2
Regarding germ line mutations associated with breast cancer susceptibility, BRCA1 and
BRCA2 are the most clinically relevant genes. Between 1 in 152 and 1 in 833 individuals
carry alterations of these genes [Iau et al. 2001]. In a combined analysis of 22 studies, the
average cumulative risks in BRCA1- and BRCA2-mutation carriers by age 50 years were 38%
and 16%, respectively, for breast cancer; by age 70 years, they were 65% and 45% [Antoniou
et al. 2003]. A number of review articles have described the structure of BRCA1 and BRCA2,
as well as the myriad of distinct mutations that can alter the function of their corresponding
proteins (see for instance [Yang and Lippman 1999; Carter 2001; Borg 2001; Iau et al. 2001;
Welcsh and King 2001; Starita and Parvin 2003; Rosen et al. 2003; Powell and Kachnic
2003, Narod and Foulkes 2004]). These data will be presented briefly here. Additional
information on BRCA1 and BRCA2 mutations may be found in the Breast Information Core
(http://research.nhgri.nih.gov/bic/)
and
Human
Gene
Mutation
(http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html) databases.
BRCA1, located at 17q21, is a large gene consisting of 24 exons spread over
approximately 80 kb of genomic DNA that encodes a transcript of 7.8 kb to produce a protein
of 1863 amino acids (220 kDa) [Miki et al. 1994]. BRCA1 shows no homology to other
known genes with the exception of a short (126 nucleotide) sequence at the N-terminus that
encodes a ring finger motif. Analysis of the mutation spectrum revealed no evidence of
clustering with an even distribution of mutations throughout the gene. This contributes to the
difficulty in mutation screening, as analysis of the complete coding sequence is required for a
thorough screen. Mutational analysis of the BRCA1 gene is therefore laborious and time
consuming.
Hereditary Breast Cancer: An Update on Genotype and Phenotype
3
Like BRCA1, BRCA2 is a large gene. Located at 13q12-13, it consists of 27 exons spread
over approximately 70 kb of genomic DNA that encodes a transcript of 12 kb to produce a
protein of 3418 amino acids (384 kDa). BRCA2 similarly shows no homology to other known
proteins, although BRCA2 exon 3 does show homology to the transcription factor c-Jun. As
observed for BRCA1, most of the mutations detected in BRCA2 induce protein truncations
that lead to loss of the protein function [Tavtigian et al. 1996]. They are also distributed
evenly along the gene, which raises the same analysis difficulties.
The proportion of HBC families that are associated with BRCA1 and BRCA2 mutations
varies widely among different populations. For instance, while BRCA1 mutations are most
commonly found in Russia (79% of breast/ovarian families) [Gayther et al. 1997], they
appear uncommon in Japan (10%) [Inoue et al. 1995]. Of note, the occurrence of BRCA1
mutations is generally greater than observed for BRCA2. There is also variation in the
population dynamics of BRCA1 and BRCA2 mutations in different countries, reflecting the
historical influences of migration and cultural and geographical isolation. Most of the
mutation-carrying families in Russia arise from two mutations (5382insC and 4135delA)
[Gayther et al. 1997] and a similar situation is found in Israel, where genotyping for ancient
mutations found that only three BRCA1 mutations (185delAG, 188del11 and 5382insC)
account for nearly all BRCA1 Jewish families [Levy-Lahad et al. 1997].
All germ line BRCA mutations identified to date have been inherited, suggesting the
possibility of a large “founder” effect in which a certain mutation is common to a welldefined population group and can theoretically be traced back to a common ancestor. Given
the complexity of mutation screening for BRCA1 and BRCA2, these common mutations may
simplify the methods required for mutation screening in certain populations. Analysis of
mutations that occur with high frequency also permits the study of their clinical expression.
A striking example of a founder mutation is found in Iceland, where a single BRCA2
(999del5) mutation accounts for virtually all breast/ovarian cancer families [Thorlacius et al.
1996, 1997]. This frame-shift mutation leads to a highly truncated protein product. In a large
study examining hundreds of cancer and control individuals, this 999del5 mutation was found
in 0.6% of the general population. Of note, while 72% of patients who were found to be
carriers had a moderate or strong family history of breast cancer, 28% had little or no family
history of the disease. This strongly suggests the presence of modifying genes that affect the
phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation
with environmental factors. Other examples of manifestations of a founder effect are among
Ashkenazi Jews. Four mutations in BRCA1 and BRCA2 have been reported to account for the
majority of Ashkenazi Jewish patients with inherited breast and/or ovarian cancer: 185delAG,
188del11 and 5382insC in the BRCA1 gene [Struewing et al. 1995; Tonin et al. 1995], and
6174delT in BRCA2 [Neuhausen et al. 1996]. In fact, it has been shown that if a Jewish
woman does not carry a BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT founder
mutation, it is highly unlikely that a different mutation will be found [Narod and Foulkes,
2004]. Additional examples of founder mutations are given in Table 1.
4
Marc Lacroix and Guy Leclercq
Table 1. A list of founder mutations
Population or
subgroup
BRCA1 mutation
BRCA2 mutation
African-Americans
943ins10, M1775R
185delAG, 188del11,
5382insC
6174delT
Ashkenazi Jewish
Austrians
Belgians
2795delA, C61G, 5382insC,
Q1806stop
2804delAA, IVS5+3A>G
Dutch
Exon 2 deletion, exon 13
deletion, 2804delAA
5579insA
Finns
3745delT, IVS11-2A>G
T8555G, 999del5,
IVS23-2A>G
French
French Canadians
Germans
Greeks
Hungarians
Icelandics
Italians
3600del11, G1710X
C4446T
5382insC
5382insC
300T>G, 5382insC, 185delAG
5083del19
9326insA
999del5
8765delAG
Japanese
L63X, Q934X
2800delAA
6503delTT
8765delAG
C61G
Northern Irish
Norwegians
Pakistanis
Polish
Russians
816delGT, 1135insA,
1675delA, 3347delAG
2080insA, 3889delAG,
4184del4, 4284delAG, IVS141A>G
300T>G, 5382insC, C61G,
4153delA
5382insC, 4153delA
2800delAA
3337C>T
6503delTT
Scottish
Slovenians
South Afrikaners
IVS16-2A>G
E881X
R71G
Spanish
Swedish
Q563X, 3171ins5, 1201del11,
2594delC
936delAAAC,
9254del5
4486delG
References
Neuhausen 2000
Struewing et al. 1995;
Tonin et al. 1995;
Neuhausen et al. 1996
Wagner et al. 1998
Peelen et al. 1997;
Claes et al. 1999
Petrij-Bosch et al. 1997;
Peelen et al. 1997;
Verhoog et al. 2001
Huusko et al. 1998;
Paakkonen et al. 2001
Muller et al. 2004
Tonin et al. 1999
Backe et al. 1999
Ladopoulou et al. 2002
Van der Looij et al. 2000
Thorlacius et al. 1996, 1997
Baudi et al. 2001;
Pisano et al. 2000
Sekine et al. 2001
The Scottish/Northern Irish
BRCA1/BRCA2
Consortium, 2003
Borg et al. 1999;
Heimdal et al. 2003
Liede et al. 2002
Gorski et al. 2000;
Perkowska et al. 2003
Gayther et al. 1997
Liede et al. 2000;
The Scottish/Northern Irish
BRCA1/BRCA2
Consortium, 2003
Krajc et al. 2002
Reeves et al. 2004
Osorio et al. 1998;
Vega et al. 2001;
Campos et al. 2003
Neuhausen 2000;
Bergman et al. 2001
Reference for mutation nomenclature: [den Dunnen and Antonarakis, 2000].
Reference for amino-acid nomenclature: [IUPAC-IUB Joint Commission on Biochemical
Nomenclature (JCBN), 1993]
Hereditary Breast Cancer: An Update on Genotype and Phenotype
5
The development of BRCA1 or BRCA2 tumours has been attributed mainly to the loss of
the DNA repair function ensured by these proteins. Indeed, both BRCA1 and BRCA2 are
involved in DNA double-strand breaks (DSB) repair. In eukaryotes, two major pathways exist
to repair DSB: non-homologous end-joining (NHEJ) and homology-directed recombination
(HR). NHEJ repairs adjacent broken DNA ends with little or no requirement for extensive
sequence homology, whereas the more accurate HR requires an intact template of a
homologous sequence either in a homologous chromosome or in a sister chromatid. HR may
occur either by “gene conversion” (GC) or by an error-prone “single-strand annealing” (SSA)
mechanism. BRCA2 is involved mainly, if not solely, in HR by GC, through its interaction
with RAD51, a key component of the DSB repair mechanism. Mutations affecting BRCA1
seem to impair both classes of HR [Moynahan et al. 1999], but BRCA1 is also possibly
involved in NHEJ by a way implying its co-localisation with the RAD50-MRE11-NBS1
complex (see notably [Zhong et al. 2002]). In addition to its importance in DSB repair,
BRCA1 could also play some role in nucleotide-excision repair (NER) (reviewed in [Tutt and
Ashworth 2002]). Thus, the involvement in DNA repair appears wider for BRCA1 than for
BRCA2.
BRCA1 and BRCA2 cannot be seen as simple components of linear chains of molecules
linking DNA alterations to DNA repair. They are increasingly recognized as members of
complex and versatile protein network(s) involved in multiple functions. BRCA1 is
associated to transcription regulation and chromatin remodelling, cell cycle and centrosome
regulation, apoptosis induction, ubiquitylation and protein degradation…Less is known on
BRCA2, except for its involvement in HR. However, there is now evidence that BRCA2 is
connected to Fanconi Anemia (FA). FA is a very rare, recessive, and complex disorder
characterised in general by congenital abnormalities, progressive bone-marrow failure and
susceptibility to acute myeloid leukaemia. Mutations in several genes (FANCA, FANCB...)
can cause FA, which defines distinct disease groups (FA-A, FA-B...). It appears that the
FANCD1 gene is indeed BRCA2. By the clinical features that they present, with Wilms’
tumours, medulloblastomas and breast cancers, FA-D1 patients tend to differ from typical FA
cases. Of interest, in FA cases in which BRCA2 mutations have been reported, these inherited
mutations affect both germ-line alleles. Curiously, two of the three bi-allelic BRCA2
mutations first noted in FA are also found monoallelically in breast/ovarian cancer families.
Thus, mutation in only one BRCA2 allele will predispose to breast/ovarian cancer syndrome,
while when both alleles are altered, providing that this is compatible with survival, the
individual will rather develop FA (reviewed in [Venkitaraman et al. 2004]).
A link between BRCA2 and sporadic breast cancers has been recently suggested by the
discovery of EMSY. EMSY is a protein which binds BRCA2 precisely within exon 3 (a
highly conserved transactivating region in the N-terminus that has endogenous transcription
repressor activity when recruited to a high basal promoter) and is capable of silencing the
activation potential of this exon, associates with several chromatin regulators, and localizes to
sites of repair following DNA damage. EMSY gene maps to chromosome 11q13.5, a region
known to be involved in breast/ovarian cancer. EMSY is amplified almost exclusively in
sporadic breast cancer (13%) and high-grade ovarian cancer (17%). However, it has not yet
been possible to show how (or if) BRCA2 is really involved in sporadic breast cancer
[Hughes-Davies et al. 2003; Rodriguez et al. 2004].
6
Marc Lacroix and Guy Leclercq
In breast cancer cells (BCC), BRCA1 and BRCA2 expression level is coupled to cell
proliferation, being highest at the G1-S phase [Rajan et al. 1996; Chen et al. 1996; Ruffner
and Verma 1997] and in proliferating cells, as compared to confluent ones [Vissac et al.
2002]. In BCC, BRCA1 and BRCA2 mRNA levels are co-ordinately elevated in response to
estrogens [Spillman and Bowcock 1996]. According to this, BRCA1 level is also induced by
prolactin (PRL) in MCF-7 and T-47D BCC [Favy et al. 1999].
While induced by mitogenic (estrogens, PRL) and/or differentiating agents (PRL),
BRCA1 appears in turn able to counteract breast cell proliferation and differentiation by
repressing oestrogen receptor (ER) [Fan et al. 1999], c-Myc [Wang et al. 1998] and STAT5a
(activated by PRL in BCC) transcription activity [Vidarsson et al. 2002]. More generally,
BRCA1 has been shown to negatively control membrane oestrogen and growth factor (EGF,
IGF-1) receptor signalling to BCC proliferation [Razandi et al. 2004]. The activity of BRCA1
on ER has been correlated with its down-regulation of the cellular levels of the transcription
co-activator p300 in BCC [Fan et al. 2002]. Of interest, p300 is also a co-activator for
STAT5a (see notably [Pfitzner et al. 1998]). These results raise the possibility that wild-type
BRCA1 suppresses oestrogen-dependent and independent transcription pathways related to
mammary epithelial cell proliferation and that loss of this property by mutant BRCA1
contributes to tumourigenesis. The potential effect of BRCA1 loss on cell differentiation is
unknown as yet [Kubista et al. 2002].
Genetic Bases of BRCAx HBC
Studies on the frequency of BRCA1 or BRCA2 mutations among HBC have clearly
revealed that a substantial part of these tumours are “non-BRCA1/BRCA2”. However, no
“BRCA3” gene has been identified to date. Part of these BRCAx lesions may be associated to
rare syndromes, of which breast cancer is only one component. Such syndromes result
notably from mutations in TP53 (Li-Fraumeni), ATM (Ataxia Telangiectasia), STK11/LKB1
(Peutz-Jeghers Syndrome), PTEN (Cowden Syndrome) (see [Iau et al. 2000; Nathanson and
Weber 2001; de Jong et al. 2002]).
Other BRCAx tumours, as well as many sporadic carcinomas, are increasingly believed
to have a “multigenic” origin, thus resulting from the expression of weakly penetrant but
highly prevalent mutations in various genes. For instance, polymorphism has been identified
in genes associated to:
1. the metabolism of various potentially toxic compounds (NAT1, NAT2, GSTM1,
GSTP1, GSTT1, CYP1A1, CYP1B1, CYP2D6);
2. the oestrogen pathway (COMT, CYP17A1, CYP19A1, ESR1, NCOA3, PR,
UGT1A1);
3. the DNA damage response pathways (CHEK2, XRCC1, XRCC3, XRCC5);
4. other processes (AR, HRAS1, VDR)
for which additional data are provided in Table 2. For reviews, see also [Weber and
Nathanson 2000; de Jong et al. 2002; Bonadona and Lasset 2003]). Sequence variants of
Hereditary Breast Cancer: An Update on Genotype and Phenotype
7
these genes that are relatively common in the population may be associated with a small to
moderate increased relative risk for breast cancer. However, combinations of such variants
could lead to multiplication effects and constitute the molecular bases for the development of
BRCAx HBC. Sporadic cancers likely result from the complex interplay between the
expression of low penetrance gene(s) (“risk variants”) and environmental factors.
Table 2. Low penetrance genes. At least one allelic variant has been associated with
increased breast cancer risk
Unigene
Name
NAT1
NAT2
GSTM1
GSTP1
GSTT1
CYP1A1
Complete protein name
Protein Function
Locus
N-acetyl transferase 1
N-acetyl transferase 2
Glutathione S-transferase M1
Glutathione S-transferase P1
Glutathione S-transferase T1
Cytochrome P450, family 1,
subfamily A, member 1
8p22
8p22
1p13.3
11q13
22q11.2
15q22-q24
CYP1B1
Cytochrome P450, family 1,
subfamily B, member 1
CYP2D6
Cytochrome P450, family 2,
subfamily D, member 6
Catechol O-methyltransferase
Cytochrome P450, family 17,
subfamily A, member 1
Cytochrome P450, family 19,
subfamily A, member 1
Oestrogen receptor
Nuclear co-activator 3
Detoxification of arylamines
Detoxification of arylamines
Detoxification of xenobiotics
Detoxification of xenobiotics
Detoxification of xenobiotics
Metabolism
of
potentially
toxic
compounds (including various aryl
hydrocarbons)
Metabolism
of
potentially toxic
compounds (including various aryl
hydrocarbons)
Metabolism
of
potentially toxic
compounds (debrisoquine, codeine,...)
Metabolism of estrogens
Metabolism of estrogens
Metabolism of estrogens
15q21.1
Response to estrogens
Steroid receptor co-activation
6q25.1
20q12
Progesterone receptor
Uridine
diphosphoglucuronosyltransferase
Checkpoint kinase 2
X-ray repair, complementing
defective, in Chinese hamster, 1
X-ray repair, complementing
defective, in Chinese hamster, 3
X-ray repair, complementing
defective, in Chinese hamster, 5
Response to estrogens
Metabolism of estrogens
11q22-23
2q37
DNA damage response and repair
DNA damage response and repair
22q12.1
19q13.2
DNA damage response and repair
14q32.3
DNA damage response and repair
2q35
Androgen receptor
V-HA-Ras Harvey rat sarcoma
viral oncogene homolog
Vitamin D receptor
Response to androgens
Signalling
Xq11-q12
11p15.5
Response to vitamin D
12q12-q14
COMT
CYP17A1
CYP19A1
ESR1
NCOA3
(AIB1)
PGR
UGT1A1
CHEK2
XRCC1
XRCC3
XRCC5
AR
HRAS
VDR
2p22-p21
22q13.1
22q11.2
10q24.3
It must be noted, however, that the suspected impact of most of these variants on breast
cancer risk should, in most cases, be confirmed in large populations studies. Indeed, low
8
Marc Lacroix and Guy Leclercq
penetrance genes cannot be easily tracked through families, as is true for dominant high-risk
genes.
The Phenotype of BRCA1, BRCA2 and BRCAx HBC
Numerous studies have allowed to collect pathobiological data on BRCA1, BRCA2 and
BRCAx tumours and to define the phenotype of these HBC subtypes [Breast Cancer Linkage
Consortium 1997; Johannsson et al. 1997; Karp et al. 1997; Osin and Lakhani 1998; Verhoog
et al. 1998; Eisinger et al. 1999; Osin et al. 1999; Noguchi et al. 1999; Phillips 2000 (+
references therein); Lakhani et al. 2000; Paredes et al. 2002; Grushko et al. 2002; Lakhani et
al. 2002; Berns et al. 2003; Foulkes et al. 2003a, 2003b; Goffin et al. 2003; Palacios et al.
2003; Sensi et al. 2003; Foulkes et al. 2004a].
A series of pathobiological characteristics of BRCA1, BRCA2, and BRCAx HBC are
summarised in Table 3.
Data from biology, pathology, and genetics, notably obtained by tissue and DNA microarray analyses, have evidenced the existence of only a few major subclasses among breast
cancers. According to this, most ER-positive, low-grade tumours may be grouped into a
“luminal (epithelial)-like” subclass, notably characterised by a high expression level of
luminal CKs (CK 8/18/19), ER, PR, BCL2, P27… a low expression level of P53 and ERBB2,
and a low-grade. Another class, known as the “ basal (epithelial)-like”, includes lesions that
are ER and PR-negative, have a low level of luminal CKs, BCL2, P27, ERBB2 and a high
expression level of P53 and of the basal CKs 5/6 and 17. Most of these tumours have a high
grade. An “ERBB2” group of tumours is also frequently found, which, as its name implies, is
exclusively composed of ERBB2-overexpressing tumours; these are generally characterised
by a low, if any, expression level of ER, PR, and P53. These three main classes (“luminallike”, “basal-like”, “ERBB2”) have been identified at both the mRNA and protein levels
[Sorlie et al. 2003; Korsching et al. 2002; van de Rijn et al. 2002; Callagy et al. 2003;
Lacroix and Leclercq 2004; Lacroix et al. 2004].
Based on their characteristics, BRCA1 tumours are clearly to be classified in the “basallike” subtype. Indeed, in a micro-array-based analysis of 115 tumours including 18 samples
from carriers of BRCA1 mutations, these latter were strongly associated with the “basal-like”
subclass. In contrast, two BRCA2 tumours were classified among the “luminal-like” group
(van’t Veer et al. 2001; Sorlie et al. 2003). Analysis of a higher number of BRCA2 tumors
should help to precise the subtype distribution pattern of these HBC.
Hereditary Breast Cancer: An Update on Genotype and Phenotype
9
Table 3. Pathobiological characteristics of HBC, as compared to unselected or sporadic
tumours
Estrogen
receptor
positivity
Progesterone receptor
positivity
Androgen
receptor
positivity
ER/PR/AR-co-positivity
(ER)(PR)(AR)-
Her-2/neu (ERBB2)-positivity
BCL2-positivity
P27-positivity
P53-positivity
Cytokeratins 8/18/19-positivity
Cytokeratins 5/6-positivity
Proliferation markers (Ki-67,
MIB1, PCNA, S-phase fraction,
mitotic count)
E-CD level
Histological type (IDC, DCIS,
ILC)
Grade
Lymph node-positivity
Microvessel count
Glomeruloid
proliferation (GMP)
Medullary cancer
vascular
BRCA1
HBC
versus unselected
or
sporadic
tumours
Less frequent in
BRCA1
Less frequent in
BRCA1
Less frequent in
BRCA1
Less frequent in
BRCA1
Less frequent in
BRCA1
Less frequent in
BRCA1
Less frequent in
BRCA1
More frequent in
BRCA1
Less frequent in
BRCA1
More frequent in
BRCA1
Higher
in
BRCA1
BRCA2
HBC
versus
unselected or sporadic
tumours
Unknown
Higher extensive
extraductal
carcinoma
BRCA1
most
frequently highgrade
Higher
BRCA1
Higher
BRCA1
More frequent
BRCA1
More frequent
BRCA1
No difference
BRCAx
HBC
versus unselected
or
sporadic
tumours
No difference
No difference
No difference
No difference
No difference
No difference
No difference
No difference or
frequent in BRCA2
No difference
less
Less frequent in
BRCAx
No difference
No difference
No difference
No difference
No difference
Less frequent in
BRCAx
Unknown
No difference
Unknown
No difference
Lower in BRCAx
Unknown
Higher
extensive
extraductal carcinoma
Lower in BRCAx
BRCAx
frequently
grade
in
No difference or BRCA2
most frequently highgrade, but only as a
consequence of decreased
tubule formation
No difference
in
No difference
Unknown
in
No difference
Unknown
in
No difference
No difference
No difference
most
low-
10
Marc Lacroix and Guy Leclercq
Genetic Analysis of BRCA1, BRCA2, BRCAx HBC
As yet, only a few studies have aimed to identify gene signatures that could be specific to
BRCA1, BRCA2, or BRCAx HBC. The data obtained need to be confirmed by additional
investigations, as the number of samples analysed was generally low.
In a micro-array analysis of primary tumours, lesions from seven carriers of a BRCA1
mutation, eight carriers of a BRCA2 mutation, and seven patients with sporadic cases of
breast cancer were considered. Statistical analyses were used to identify a set of genes that
could distinguish the BRCA1 genotype from the BRCA2 genotype. Permutation analysis of
multivariate classification functions established that the gene-expression profiles of tumours
with BRCA1 mutations, tumours with BRCA2 mutations, and sporadic tumours differed
significantly from each other. An analysis of variance between the levels of gene expression
and the genotype of the samples identified 51 genes that best differentiated among the three
types of tumours [Hedenfalk et al. 2001]. This suggests that either a heritable mutation
influences the gene expression profile of the cancer, or specific mutations are viable only in a
specific gene environment. Of note, and maybe as a consequence of the low number of
tumours, the gene signature specifically associated to BRCA1 HBC did not appear to
constitute a part of the “basal-like” signature. However, as expected, the expression of the
luminal CK 8 gene was low in these lesions, in accordance with previous data. On the other
hand, among genes more highly expressed in BRCA1 HBC, as compared to BRCA2, were
some that are known to be induced by P53 in response to DNA damage: GADD34, MSH2,
MSH6... As P53 is mutated in a majority of BRCA1 tumours, this raises the possibility of a
P53-independent activation of DNA damage response pathways in these HBC. This
observation is also in agreement with the fact that the role of BRCA1 in DNA repair is more
extended than is the case for BRCA2.
Since the BRCAx HBC comprise a histopathologically heterogeneous group, it has been
suggested that these tumours may originate from multiple distinct genetic events. As intensive
efforts have not allowed the identification of BRCAx predisposition genes, attempts have been
made to identify distinct and specific genetic signatures. In a small series (n=16) of BRCAx
tumours, gene expression profiling identified at least two classes, and differentiated them
from BRCA1 and BRCA2 HBC. Moreover, micro-array-based comparative genomic
hybridisation (CGH) to cDNA arrays revealed specific somatic genetic alterations within the
BRCAx subgroups [Hedenfalk et al. 2003].
BRCA1 and p53
One of the numerous proteins able to interact with BRCA1 is P53. This transcription
factor plays a key role in defining the cellular responses to DNA damage, by activating the
expression of genes involved in cell-cycle arrest or apoptosis. However, the molecular
mechanisms presiding to the initiation of one process rather than the other remain largely
unknown. Many factors, including cell type as well as expression levels of P53 and other
survival factors, are believed to be important for this decision.
Hereditary Breast Cancer: An Update on Genotype and Phenotype
11
Loss of BRCA1 function in cells appears to activate a P53-dependent response, as
illustrated by the partial phenotypic rescue observed when homozygous Brca1null mice are
crossed to a P53-deficient background (Tp53-/-). Homozygous Brca1null embryos die around
6.5 days post coitus (dpc) due to a cell-cycle block and up-regulation of the P53-activated
cell-cycle regulator p21. Crossing Brca1null mice with Tp53-/- mice to generate
Brca1null/null/Tp53-/- embryos reveals that in the complete absence of P53, the lethality due to
BRCA1 deficiency is postponed to 9.5–10.5 dpc [Hohenstein and Giles 2003]. This indicates
that, at least in some cases, cell survival after BRCA1 mutation could require an alteration of
P53. Along the same line, conditional knockout of Brca1 in mouse mammary epithelium
generates breast tumours in 25% of mice. The additional loss of P53 results in the
development of breast tumours in 50% of these mice [Brodie et al. 2001]. Again, these data
strongly suggest that loss of P53 is important for the development of BRCA1 HBC. Studies
have shown that over-expression of an abnormal P53 resulting from TP53 mutation is much
more frequent in BRCA1 tumours than in non-HBC and in non-BRCA1 HBC. For instance,
54%, 0% and 5% of P53 alterations were found in BRCA1-, BRCA2 and BRCAx tumours,
respectively [Sensi et al. 2003]. If, as is the case in mouse embryos, BRCA1 deficiency in
human breast tissue activates a P53-dependent checkpoint, a strong selective pressure to
somatically inactivate P53 in the tumour will result.
As BRCA1 is involved in DNA repair, it is possible that its inactivation by mutation
could explain, at least partly, the high frequency of P53 mutations observed in BRCA1
lesions. However, a high level of P53 expression is indeed characteristic of the “basal-like”
subtype of breast tumours, no matter whether they have or not a mutation in BRCA1, and this
reflects indeed a higher genetic instability in this subtype of lesions [Lacroix et al. 2004]. On
the other hand, a role of BRCA1 in generating TP53 mutations is suggested by the fact that
the mutation spectrum of TP53 is different in BRCA1 tumours, as compared to sporadic, both
in mutation distribution and base changes. In BRCA1 HBC, changes are common at TP53
codons that are not mutation hot spots. Most of the resulting “non-hot-spots amino-acids” are
physically clustered and are distributed in a region of the protein on the opposite side of the
DNA-binding surface [Greenblatt et al. 2001]. This suggests that the development of BRCA1
lesions might need the modification of the interaction(s) between P53 and one or several
regulatory protein(s).
It has been proposed that BRCA1 could serve as a molecular scaffold, assembling
proteins involved in the fine-tuning of the P53 response, such as ATM, CHK2 and p300.
Depending on the (maybe p300-mediated) acetylation of its C-terminus [Hohenstein and
Giles 2003], P53 binding to DNA sequences could induce cell cycle arrest or apoptosis. A
truncated BRCA1 could render a normal P53 unable to arrest cell cycle, while still allowing it
to trigger apoptosis. Mutation of P53 could in turn prevent apoptosis, blocking thus any
action of P53. A P53-interacting region of BRCA1 is situated in the C-terminal region of the
protein, which is frequently truncated after mutation.
While P53 mutations could contribute to the development of BRCA1 lesions, they are
clearly not required to generate BRCA2 or BRCAx HBC.
12
Marc Lacroix and Guy Leclercq
BRCA1 and ER-Negativity
Why are BRCA1 tumours so frequently ER-negative?
It has been suggested that this be due to the fact that these lesions occur frequently in
young women. Indeed, sporadic tumours occurring at an early age are more likely to be ERnegative than tumours observed in post-menopausal patients. However, in a large study of
women with invasive breast cancer, it appeared that BRCA1-mutation carriers were more
likely to be ER-negative breast cancers than were women in other groups, after adjustment for
age, grade, and histological subtypes [Foulkes et al. 2004c].
The reasons behind the preferential “basal-like”, ER-negative phenotype of BRCA1 HBC
are still a matter of speculation.
One hypothesis is that loss of BRCA1 activity could lead to down-regulation of the ER at
a specific time in the development of BRCA1 cancers. This would, indeed, imply extended
changes in gene expression patterns, as micro-array data indicate that most ER-positive
tumours are “luminal-like”, while most BRCA1 tumours are “basal-like”. These two tumour
subtypes are characterised by highly different gene signatures. It was previously believed that
during progression, breast cancers could evolve from a differentiated, ER-positive, “luminallike”, to a dedifferentiated, ER-negative, “basal-like” portrait. It was hypothesised that
successive clonal expansions inside the tumour mass could in fine lead to a phenotype
conversion. However, it increasingly appears that a phenotype drift from a “luminal-like” to a
“basal-like” portrait is rare during progression (Lacroix et al. 2004). It could, however, occur
very early in the development of the lesion and cannot be excluded as yet.
Along the same line, it has been suggested that BRCA1 activity could be needed to
promote an orderly transition of breast cells from a “primitive” “basal-like” phenotype,
reminiscent of a breast stem cell portrait, to a “luminal-like” (glandular) phenotype, which is
expected in most terminally differentiated cells. BRCA1 loss could prevent this transition
[Foulkes 2004b]. Research on breast cancer stem cells represents a rapidly developing field
(see notably [Dontu et al. 2004]), and future investigations will certainly contribute to clear
this possible role of BRCA1.
Another hypothesis is that, in contrast to “basal-like” cells, “luminal-like” ER-positive
BCC could be unable to survive their loss of BRCA1 activity. As mentioned above, BRCA1
level is increased by estrogens in breast cancer cells and the protein is a repressor of ER
transcription activity [Dobrzycka et al. 2003]. In absence of BRCA1 activity, ER-positive
cells could be subject to an uncontrolled proliferation process allowing the multiplication of
non-corrected genetic alterations. Estrogens and their metabolic products might cause genetic
instability, perhaps by inducing free radical-mediated DNA damage and mutations [Liehr
2000; Yue et al. 2003; Miller 2003; Mobley and Brueggemeier 2004; Russo and Russo
2004]. A lack, or a deficiency, of BRCA1 activity in ER-positive cells could prevent the
correct repair of DNA damages [Hilakivi-Clarke 2000], leading in fine to cell death. As
mentioned above in this chapter, the involvement of BRCA1 in DNA repair is wide, as
compared to BRCA2. This could explain why ER-positive cells lacking BRCA2 activity
remain viable.
An implication of BRCA1 in X chromosome silencing has been suggested. Indeed,
mutation, or loss of function of BRCA1 results in an altered phenotype of X chromosome
Hereditary Breast Cancer: An Update on Genotype and Phenotype
13
inactivation, a process by which a major heterochromatin domain is established over one X
chromosome. XIST is an RNA molecule that coats the inactive X chromosome in female cells
and is central to the process by which the entire chromosome is repressed (for a review, see
[Andersen and Panning 2003]). When BRCA1 is not expressed in a cell, XIST RNA fails to
localise to the X chromosome. The presence or absence of functional BRCA1 does not affect
the level of the XIST transcript, just its localisation and effectiveness in silencing [Ganesan et
al. 2002]. Whether the XIST RNA localisation phenotype might promote breast cancer of
explain the basal phenotype (see below) of BRCA1 cancers remains, however, unknown. We
can hypothesise that de-repressed X chromosome could express some oncogene at higher
levels than in cells that have one inactivated X chromosome. It is also possible that a gene
product expressed only in BRCA1 tumours could prevent the development of the luminal
epithelial phenotype or even contribute to reverse it.
BRCA1 and Oestrogen Sensitivity: Paradoxical
Relationships
As summarised below, the expression spectrum of most biological markers appears very
similar in BRCA2 HBC and in sporadic tumours. In contrast, the phenotype of BRCA1 HBC
is basal-like (and thus ER-negative) in the vast majority of cases. This suggests that the
development of BRCA1 tumours is largely incompatible with hormone-sensitivity.
On the other hand, there are data suggesting a specific positive association between the
occurrence of BRCA1 carcinomas and a high oestrogen level:
1. In a combined analysis of 22 studies, the relative risk of breast cancer was shown to
decline significantly with age (after 49 years) in BRCA1-, but not in BRCA2mutation carriers [Antoniou et al. 2003]. This suggests that the high oestrogen levels
characterising pre-menopause could favour the development of BRCA1 HBC.
2. Contrasting with BRCA2-mutation carriers, no increased incidence of breast cancer
is observed in men heterozygous for BRCA1 mutations [Liede et al. 2004].
Circulating oestrogen levels are low in men and most of the male breast tumours are
ER-positive, as also observed in post-menopausal women [Anderson et al. 2004].
3. BRCA1-mutation carriers are also predisposed to cancer of the ovary, another organ
subjected to estrogenic regulation. In fact, BRCA1 mutations appear to make little
contribution to cancer risk aside from breast and ovarian cancer. The situation
contrasts remarkably in the case of BRCA2 mutations, which have been linked to
cancers of the pancreas and prostate, as well as ocular melanoma [Iau et al. 2001].
4. BRCA1-mutation carriers are particularly susceptible to develop a breast cancer as a
result of pregnancy [Jernstrom et al. 1999], which is well known to increase
circulating oestrogen levels (by approximately 10-fold).
5. Prophylactic oophorectomy in BRCA1-mutation carriers, resulting in oestrogen
deprivation, led to highly significant 47% reduction in the risk of breast cancer
[Rebbeck et al. 1999].
14
Marc Lacroix and Guy Leclercq
6. In general, hormone-based treatments, such those using the anti-oestrogen
tamoxifen, are unable to prevent or treat ER-negative breast cancers [Early Breast
Cancer Trialists' Collaborative Group 1992; Fisher et al. 1998] and doubts have thus
been expressed about the efficacy of hormonal chemo-prevention for BRCA1
tumours [Lakhani et al. 2002]. Surprisingly, in a large retrospective case-control
study of BRCA1-mutation carriers with or without contra-lateral breast cancer,
tamoxifen was highly effective in preventing second primary cancer in BRCA1mutation carriers [Narod et al. 2000]. According to another study, tamoxifen
appeared to be effective in reducing both local recurrence and contra-lateral breast
cancer among women with BRCA1 mutations [Metcalfe et al. 2004].
In this paper, the term “ER “ stands for “ER-alpha”. This iso-form of the receptor has
been evaluated in tumours (including HBC) for more than 30 years and its essential role in
breast cancer biology is well established. ER-alpha expression is strongly associated to the
“luminal-like” and constitutes indeed the main discriminator in breast tumour classification
(for a review, see [Lacroix and Leclercq 2004; Lacroix et al. 2004]. ER-alpha was long
believed to be unique, until an iso-form named ER-beta was identified [Palmieri 2000].
According to various reports, ER-alpha seems to be the most abundant and functionally the
most important in breast tumours (see for instance [Dowsett and Ashworth 2003]). However,
the exact role of ER-beta is still under investigation. ER-beta has notably been described to
act as a dominant negative regulator of ER-alpha-mediated transcription, thus attenuating
massive estrogenic stimulation [Hall and McDonnell 1999] The role of ER-beta in favouring
the antagonistic effect of anti-estrogens is supported by the association between protein
expression and favourable outcome after tamoxifen treatment [Mann et al. 2001].
It has been proposed that the presence of ER-beta could explain, at least in part, the
responsiveness of BRCA1 carcinomas to estrogens/anti-estrogens [Daidone et al. 2002]. In an
immuno-histochemical analysis ER-beta positivity was observed in 84% (37/44) of familial
breast cancer compared with 69% of non-familial cases matched for age and year of initial
diagnosis. Despite its presence, it seems unlikely that ER-beta could exert any effect by
regulating negatively the action of ER-alpha, since this latter is very rare in BRCA1 tumours.
ER-beta might play a role that does not need the presence of ER-alpha. It has recently been
suggested that ER-beta is localised in the mitochondrion, and could thus play a role in
regulating the oxidative metabolism [Yang et al. 2004]. Mitochondria are central in the
regulation of cytoplasmic redox state. Oestradiol can protect against ATP depletion,
mitochondrial membrane potential decline, and the generation of reactive oxygen species
induced by 3-nitroproprionic acid [Wang et al. 2001]. ER-beta could allow reducing the
generation of free radicals [Yang et al. 2004].
To explain the responsiveness of BRCA1 HBC to estrogens/anti-estrogens, another
possibility must be taken into consideration, although it remains purely speculative to date.
The first BRCA1-mutated “basal-like” (and thus ER-negative) mammary tumour cells could
be protected from (possibly P53-mediated) apoptosis by factors secreted by their
neighbouring “luminal-like”, ER-positive normal cells in response to estrogens. Antiestrogens could prevent this effect. However, how to explain that these tumour cells could
continue to proliferate in the growing lesion when the relative abundance of the surrounding
Hereditary Breast Cancer: An Update on Genotype and Phenotype
15
“luminal-like” ER-positive normal cells decreases? We propose that the tumour cells could
progressively escape their need for exogenous factors, possibly as a consequence of TP53
mutation.
Conclusion
It increasingly appears that a few “portraits” may be found among breast tumours. The
subclasses that they defined are characterised by specific gene and marker expression
profiles.
BRCA1 carcinomas are mainly, if not exclusively, “basal-like” at both the genotype and
phenotype levels. The mechanisms underlying this restricted distribution are far from being
understood, but they are likely related to the complex involvement of BRCA1 in proliferation,
differentiation, and apoptosis processes. This implication is notably illustrated by the coordinate control exerted by BRCA1 on ER, Stat5a, and P53 activity, and, more generally, on
growth factor signalling, in “luminal-like” epithelial cells. In line with this, one factor
deserving further investigations is p300. This histone acetyltransferase may interact with
BRCA1, P53, ER, Stat5 and is considered to play a central role in co-ordinating and
integrating multiple signal-dependent events with the transcription apparatus [Chan and La
Thangue 2001]. The loss of control of p300 by BRCA1 could trigger mechanisms ultimately
leading to apoptosis in “luminal-like” but not in “basal-like” cells.
As observed with sporadic carcinomas, most BRCA2 and BRCAx HBC express the
features of the “luminal-like” phenotype. Further genetic studies should precise the
distribution of these tumours among subtypes, as well as to further resolve the heterogeneity
of BRCAx HBC.
No BRCA3 gene has been associated to the non BRCA1/BRCA2 HBC as yet. Despite
their heterogeneity, these lesions seem to be less aggressive than sporadic cancers. The
clustering of breast cancer in BRCAx families probably does not result from the presence of
highly penetrant allele(s), but rather from a mixture of many interacting genes and chance.
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