www.thelancet.com/oncology Vol 13 December 2012 e537
Lancet Oncol 2012; 13: e537–44
Department of Human
Molecular Genetics and
Biochemistry, Sackler School of
Medicine, Tel Aviv University,
Tel Aviv, Israel
(Prof H Werner PhD); and
Gynecologic Oncology Unit,
Department of Obstetrics and
Gynecology, Meir Medical
Center, Kfar Sava, Israel
(I Bruchim MD)
Prof Haim Werner, Department
of Human Molecular Genetics
and Biochemistry, Sackler School
of Medicine, Tel Aviv University,
Tel Aviv 69978, Israel
IGF-1 and BRCA1 signalling pathways in familial cancer
Haim Werner, Ilan Bruchim
The insulin-like growth factor (IGF) system has a direct eff ect on cellular proliferation and survival, and interacts with
genetic and environmental factors implicated in causing cancer. Experimental, clinical, and epidemiological evidence
show that the IGF signalling pathways are important mediators in the biochemical and molecular chain of events that
lead from a phenotypically normal cell to one harbouring neoplastic traits. BRCA1 and BRCA2 have an important role
in the development of hereditary and sporadic breast and ovarian cancer. Recent evidence suggests that risk of cancer
conferred by BRCA mutations can be modifi ed by genetic and environmental factors, including ambient
concentrations of IGF-1 and polymorphisms in IGF system components. This Review addresses interactions between
the IGF and BRCA1 signalling pathways, and emphasises the convergence of IGF-1-mediated cell survival, proliferative
pathways, and BRCA1-mediated tumour protective pathways. Understanding the complex interactions between these
signalling pathways might improve our understanding of basic molecular oncology processes and help to identify
new molecular targets, predictive biomarkers, and approaches for optimising cancer therapies.
Breast cancer is the most frequently diagnosed
oncological disease and the leading cause of death related
to malignancy among women. With almost 1∙4 million
new cases annually, breast cancer accounts for 23% of
the total cancer cases and 14% of cancer deaths
worldwide.1 Historically, population-based risk factors,
including older age at
socioeconomic status, and fi rst-degree family history of
breast cancer, were associated with less than half of
breast cancer cases.2 Cellular and molecular mechan isms
were sought to explain breast cancer development and
progression, particularly the association with oes trogen
receptor (ER) signalling pathways.3 Proliferation of breast
epithelial cells is also responsive to various peptide
growth factors.4 The insulin-like growth factor (IGF)
system has a major role in development of breast
cancer—evidence shows that IGFs are mediators in the
chain of events by which phenotypically normal cells
adopt neoplastic traits.5–8
The IGF axis constitutes a network of secreted ligands
(insulin, IGF-1, IGF-2), cell-surface receptors (insulin
receptor, IGF-1 receptor [IGF1R]), and IGF-binding
proteins (IGFBPs) that regulate metabolic, nutritional,
endocrine, growth, and ageing events, among others.
IGF1R, which mediates the biological actions of IGF-1
and IGF-2, shows potent antiapoptotic and, potentially,
transforming activities, and is considered a key factor
in cancer development.9,10 IGF1R has emerged as a
promising therapeutic target, and eff orts are underway
to translate experimental and preclinical data into
standard medical protocols.11–14 In addition to its direct
eff ect on cellular proliferation and survival, the IGF
network interacts with several genetic and environmental
factors that have been implicated in development of
breast cancer. This Review examines interactions of the
IGF axis with BRCA1 and BRCA2, a family of high-
penetrance genes with key roles in familial cancer.
Analysis of the interplay between IGF and BRCA
signalling pathways might shed light on important
questions in modern oncology.
fi rst birth, nulliparity,
Endocrine IGF-1 and cancer risk: analysis of
The potential association between circulating IGF-1
concentrations and breast-cancer risk is a controversial
issue.7,15 Large-scale epidemiological studies suggested
that high circulating IGF-1 concentrations were asso-
ciated with increased risk for several types of cancer,
including breast and prostate.16,17 In a prospective, nested
control study (the Nurse’s Health Study),17 premeno-
pausal women with high IGF-1 concentrations (upper
tertile) had a relative risk of breast cancer of 4∙6, com-
pared with premenopausal women who had low IGF-1
concentrations (lower tertile). Furthermore, the relative
risk increased to 7∙3 when concentrations of IGFBP-3
were included in the ana lysis.17 In this study, IGF-1
concentrations were measured an average of 7 years
before disease diagnosis. Several subsequent epi-
demiological studies reported diverse (and sometimes
opposing) outcomes.18–20 A comprehensive meta-analysis
by Clayton and colleagues21 concluded that circulating
IGF-1 values are positively associated with risk of pros-
tate, premenopausal breast, and colorectal tumours,
although the relative risks were substantially lower than
those reported in earlier studies. Similarly, the Endogen-
ous Hormones and Breast Cancer Collaborative Group,
in an analysis of 17 prospective studies from 12 countries,
reported that IGF-1 is positively associated with breast
cancer risk.15 By contrast with Clayton and colleagues’
analysis, the association of IGF-1 with breast cancer was
not substantially modifi ed by IGFBP-3 and was not
aff ected by menopausal status; however, the association
was confi ned to ER-positive tumours. Taken together,
these epidemiological observations could have major
implications for risk assessment and cancer prevention.
Studies have shown that the IGF1R gene is expressed
in 39–93% of primary breast carcinomas ; however, data
are confl icting regarding the diagnostic and prognostic
signifi cance of these values.22 Most data are consistent
with the notion that IGF1R expression is lower in benign
lesions and normal breast tissue than in malignant
tissue.23 However, several studies have suggested that as
www.thelancet.com/oncology Vol 13 December 2012
breast cancer progresses it becomes IGF independent
(probably associated with oestrogen independence).24,25
As a result, IGF1R expression levels are reduced and
become inversely associated with tumour progression.
A recent study of 2871 patients with breast cancer showed
that IGF1R expression was associated with age older than
50 years, lower histopathology grade, ER positivity, and
HER2 negativity.26 This study clearly established that
IGF1R correlates with good prognostic variables (ie,
markers predicting breast cancer-specifi c survival)
among patients with early disease. Furthermore, IGF1R
is diff erentially expressed with varying prognostic impact
among breast cancer subtypes.26
Role of IGF1R in malignant transformation
Several mechanisms have been proposed to explain the
role of the IGF axis in initiation and progression of
neoplasia. Typical features of the IGF1R include potent
antiapoptotic and mitogenic capacities, important roles
in invasion, metastasis, and angiogenesis, and involve-
ment in oncogenic transformation.5,8,27,28 The IGF sys tem,
including IGF1R, is not oncogenic per se; the ligand-
activated receptor is not genotoxic and is unable to
induce mutations or other types of DNA damage. Rather,
IGF-1 functions as a progression factor capable of
pushing cells, including already transformed cells,
through the cell cycle.
The idea that IGF1R expression is a prerequisite for
acquisition of a malignant phenotype is widely accepted,10
and is based on realisation that raised IGF1R levels and
enhanced IGF signalling are indispensable for the cell to
adopt proliferative and oncogenic pathways. However,
this paradigm is not necessarily valid for every type
of cancer. IGF1R overexpression is common in most
paediatric tumours, which are often associated with
recurrent chromosomal translocations, and in other solid
tumours, such as brain and renal cancers, but the
situation in adult epithelial tumours (eg, prostate and
breast) is more complex. IGF1R is a target for oncogene
and tumour suppressor action, and the mechanisms of
action of several cancer genes (eg, TP53, VHL, WT1)
involve transcriptional modulation of the IGF1R promoter
or activation of the receptor tyrosine-kinase domain.29
BRCA1 and BRCA2 in hereditary breast–ovary
Inactivating germline mutations within BRCA1 and
BRCA2 are detected in a large proportion of families with
inherited breast or ovarian cancer.30 Mutation carriers
have an increased lifetime risk of developing breast
(40–85%) and ovarian (16–64%) cancer.31,32 In most
ethnically diverse, high-risk families, BRCA1 germline
mutations are private, family specifi c, and are scattered
throughout the gene, with no particular hot spots. In
Jewish Ashkenazi women,
185_186delAG and 5382_5383insC are the only molecular
defects described in BRCA1.33
Complex regulation of BRCA1 and IGF1R
IGF1R has been identifi ed as a molecular target for
BRCA1 action.29 Consistent with its tumour suppressor
role, wild-type BRCA1 expression led to a marked
decrease in IGF1R promoter activity and endogenous
IGF1R levels in breast-cancer cell lines.34 However, a
mutant BRCA1 encoding a truncated version of the
molecule (185_186delAG) had no eff ect on IGF1R
expression.35 The paradigm that emerges is that activation
of BRCA1 after DNA damage, oxidative stress, or other
cellular insult could lead to transcriptional suppression of
IGF1R expression, with an ensuing reduction in IGF1R
activation by endocrine IGF-1 or locally produced IGF-1 or
IGF-2. Abrogation of IGF1R signalling might favour
apoptotic and cell-protecting pathways—ie, the pro-
totypical mission of a tumour suppressor. In familial
cancer, loss-of-function mutation of BRCA1 might abolish
its tumour protective function, leading to constitutive
activation of the IGF1R signalling pathway, a typical
hallmark of cancer cells. In addition to breast cancer,
transcriptional suppression of the IGF1R gene by BRCA1
has been reported in prostate and endometrial cancer.36,37
Gel shift assays have not shown binding of BRCA1 to
the IGF1R promoter, in accordance with studies showing
that, in general, BRCA1 is not a DNA-binding protein.
However, BRCA1 was able to bind with high affi nity to
zinc-fi nger protein SP1, a member of the transcription
machinery, and prevent it from binding and transacti-
vating the IGF1R promoter.35 Additionally, the transcrip-
tional activity of BRCA1 depends on the cellular status
of P53. BRCA1 and P53 were shown to associate in
coimmunoprecipitation assays, and BRCA1 was able to
suppress IGF1R transcription in both P53-expressing
and P53-null cellular backgrounds, but not in mutant
P53-containing cells.38 Therefore, loss-of-function muta-
tion of the TP53 gene, a common event in human cancer,
might result in inability of BRCA1 to suppress IGF1R
expression, with major clinical implications.
Although inactivating BRCA1 germline mutations
substantially increase breast and ovarian cancer risk,
little is known about the cellular and circulating factors
involved in regulation of BRCA1 expression. Develop-
mental analyses have shown that BRCA1 is highly
expressed in rapidly proliferating cells,39 and expression
is stimulated by positive signals at the cell cycle point
where cells become committed to replicating their DNA
and undergoing cell division.40 BRCA1 expression is high
during the prereplicative (G1) phase, and BRCA1 is
involved in control of the G1–S and G2–M transition
checkpoints.41 Evidence of a close interplay between the
IGF-1 and BRCA1 pathways was provided by studies
showing that IGF-1 and IGF-2 enhance BRCA1
expression in a dose-dependent manner.42 Abrogation of
BRCA1 action leads to roughly a doubling in the IGF-1-
induced proportion of cells arrested at G0, and a decrease
of about a third in the proportion of cells at M phase.42
Since IGFs regulate cell division by controlling events
www.thelancet.com/oncology Vol 13 December 2012 e539
that occur mainly during G1, it is reasonable to assume
that at least some IGF actions are mediated by BRCA1.
Additionally, trans fection experiments using BRCA1
promoter fragments fused to a luciferase reporter
showed that the eff ect of IGF-1 on BRCA1 expression was
mediated at the transcriptional level.42 Similar to
repression of the IGF1R promoter by BRCA1, activation
of the BRCA1 promoter by IGF-1 involves enhanced SP1
binding to cis-elements in the promoter. AKT, a
downstream mediator of IGF-1 action, was shown to
regulate BRCA1 stability independent of new protein
synthesis, suggesting that IGF-1 signalling modulates
BRCA1 abundance at various control levels.43 These
studies suggest that a feedback loop controls expression
and action of the IGF-1 and BRCA1 signalling pathways
in a synchronised manner. Deregulated expression of
BRCA1 as a result of aberrant IGF signalling might have
consequences in breast cancer development.
BRCA1-mutant breast tumours show increased
An association between somatic IGF1R expression and
BRCA1 status in breast cancer has been described.44
Immunohistochemical analyses of 36 primary breast
tumour specimens (11 tumours from patients with
185_186delAG BRCA1 mutation and 25 specimens
from patients who tested negative for four common
BRCA1 and BRCA2 mutations) showed that IGF1R
expression was twice as high in tumours from BRCA1
mutation carriers as it was in tumours from non-
BRCA1 mutation carriers (ie, sporadic tumours).
Additionally, surrounding healthy breast tissue from
the BRCA1 mutation carriers showed higher IGF1R
levels than similar tissue from non-carriers.44 The
capacity of wild-type, but not mutant, BRCA1 to inhibit
IGF1R biosynthesis might provide an explanation for
the lower IGF1R levels seen in tumours from non-
BRCA1 mutation carriers, and for the reduced
mitogenic activity in wild-type BRCA1-expressing cells
(fi gure 1). Voskuil and colleagues45 showed that
concentrations of some IGF system components,
including IGF1R mRNA, in healthy and malignant
breast tissues were higher in individuals with a strong
family history of breast cancer (usually asso ciated with
BRCA1 or BRCA2 mutations) than in individuals with
no such history. Finally, support for the notion that
BRCA1 can also control expression of the IGF-1 ligand
was provided by studies showing that intratumoral
IGF-1 concentrations were upregulated in tumours
from BRCA1 or BRCA2 mutation carriers, compared
with concentrations in matched sporadic tumours.46
Analysis of ER status in BRCA1-associated tumours
showed that only 27% (three of 11) BRCA1 mutation
carriers were ER-positive, compared with 96% (24 of 25)
non-carriers.47 These results are concordant with
extensive data showing that breast cancers in patients
with BRCA1 mutations are more often ER-negative
than tumours from non-carriers.48 Additionally, mutant
BRCA1 tumours are often progesterone receptor (PR)
and HER2 negative (ie, triple negative), usually associated
with P53 muta tions, and present with a higher
malignancy grade.49 The absence of ER in mutant BRCA1-
associated cancers might be evidence of hormone
independence of BRCA-asso ciated familial breast
cancer.48 Eerola and colleagues50 reported that tumours
from BRCA1 or BRCA2 mutation carriers aged 50 years
or older diff ered from tumours in younger carriers in
terms of histology, grade, ER, PR, P53, and HER2 status.
These diff erences might refl ect diff erent biological
behaviours and pathways of tumour development in
older compared with younger BRCA-mutant patients,
with a potential eff ect on prognosis and survival.
Role of steroid hormones in BRCA1 and IGF-1
The IGF-1 and BRCA1 signalling pathways are closely
interconnected with cellular paths that mediate steroid
hormone action. For example, BRCA1 inhibited the
estradiol-inducible transcriptional activity of ERα in
breast and prostate cancer cells, whereas cancer-
associated BRCA1-mutant cells did not show inhibited
ERα activity.51,52 The reciprocal activity, enhancement of
BRCA1 expression by oestrogens, seems to be a result of
the mitogenic activity of oestrogens, although studies
have suggested that estradiol directly stimulates the
Figure 1: Model for negative regulation of IGF1R gene expression by BRCA1
(A) IGF1R expression is heavily dependent on a family of zinc-fi nger transcription factors, including SP1, which bind
GC boxes in the proximal promoter region and stimulate gene transcription. TBP nucleates the basal transcription
machinery at the initiator element, a promoter motif from which transcription starts in vivo. IGF1R expression is
usually linked to cell cycle progression. (B) After DNA damage or other cellular insults, BRCA1 interacts with and
prevents SP1 from binding to the IGF1R promoter, and P53 binds to TBP, disrupting formation of the transcription
initiation complex. (C, D) Quantitative evaluation of IGF1R immunostaining revealed a higher score in
185_186delAG mutant BRCA1-associated tumours (C) than in tumours from non-carriers (D): mean 4·6 (SE 0·5)
versus 2·6 (0·2); p<0·002. Panels C and D were reproduced with permission from reference 44. TBP=TATA-box
binding protein. POL=RNA polymerase II.
Cell cycle progression
185_186delAG BRCA1-carrier tumour Non-BRCA1-carrier tumour
Normal proliferating cellBRCA1 induction
www.thelancet.com/oncology Vol 13 December 2012
BRCA1 promoter.48,53 Likewise, oestrogens were shown to
strongly transactivate the IGF1R promoter in ER-positive,
but not ER-negative, breast cancer cells.24 Chromatin
immunoprecipitation assays revealed that part of
oestrogen’s eff ect on IGF1R expression was mediated
through activation of the SP1 transcription factor.
Combined clinical and experimental data em phasise the
complexity of the functional interactions between
BRCA1, IGF-1, and ER signalling pathways (fi gure 2),
and the multifaceted biological regulation required to
modulate these processes.
Is IGF-1 a breast-cancer risk modifi er among
BRCA1 mutation carriers?
Risk estimates for breast cancer in women who carry
mutations for BRCA1 or BRCA2 range from 20–80%,
suggesting that penetrance of the BRCA genotype is
dependent on genetic or environmental risk modifi ers,
or both.54 The IGF-1 signalling pathway has been
identifi ed as an important modifi er of BRCA1 action.
Neuhausen and colleagues55 did a single nucleotide
polymorphism (SNP) analysis of IGF-1, IGF1R, IGFBP-1,
IGFBP-2, IGFBP-5, and IRS1 in a cohort consisting of
1122 BRCA1 mutation carriers (433 breast cancer cases)
and 543 BRCA2 carriers (238 cases), and performed Cox
proportional-hazards regression analyses for time from
birth to diagnosis of breast cancer for mutation carriers.
The study identifi ed a signifi cant association among
BRCA1 carriers between risk of breast cancer and linkage
disequilibrium blocks in IGF1R. Among BRCA2 carriers,
a linkage disequilibrium block in IGFBP-2 was associated
with time to breast cancer diagnosis. No signifi cant
associations between breast cancer risk and linkage
disequilibrium block were found for the other genes. In a
second study, Neuhausen and colleagues56 identifi ed a
signifi cant association between breast cancer risk and
linkage disequilibrium blocks in the IGF-2 gene. A
recent study based on 209 cases and 99 controls
suggested that serum concentrations of IGF-1 might be a
risk factor for breast cancer among BRCA mutation
carriers.57 However, no association between IGF-1
concentrations and early diagnosis in BRCA mutation
carriers was reported in a Swedish cohort.58 The
associations are unclear (panel).
Klotho is a transmembrane protein that acts as a
circulating hormone after shedding from the cell
membrane. It has been identifi ed as a candidate tumour
suppressor in breast and pancreatic cancers. Wolf and
colleagues59 examined the role of klotho as a cancer-risk
modifi er, by investigating an association between
KL-VS, a functional variant of klotho containing two
aminoacid substitutions (Phe352Val and Cys370Ser),
and breast cancer among Jewish Ashkenazi women
with BRCA1 or BRCA2 mutations. Among BRCA1
carriers, heterozygosity for the KL-VS allele was
associated with increased risk of breast and ovarian
cancer (hazard ratio [HR] 1∙4 for each) and younger age
at breast cancer diagnosis (median age 43 vs 48 years).
Additionally, klotho and BRCA2 are located at 13q12, and
a linkage disequilibrium between KL-VS and BRCA2
6174delT mutation was noted.59 Studies in breast cancer
cells showed reduced inhibitory growth activity and
reduced secretion of klotho Phe352Val compared with
wild-type klotho.59 Hence, klotho KL-VS can be
considered a risk modifi er for breast and ovarian cancer
among BRCA1 mutation carriers. Klotho has also been
shown to modulate IGF-1 action; forced expression of
klotho or addition of soluble klotho to cultured breast
cancer cells inhibited activation of the IGF-1 pathway,
and coimmunoprecipitation assays showed a physical
interaction between klotho and IGF1R.60 Therefore, the
ability of klotho to modify cancer risk among BRCA1
mutation carriers might refl ect its biological interaction
with the IGF-1 signalling pathway.
Metabolic consequences of the BRCA1–IGF-1 link
Hyperinsulinaemia and obesity are well known risk
factors for breast cancer. The epidemiological correl ations
are very complex; obesity is associated with increased
cancer risk in postmenopausal women, but not in
premenopausal women.21 However, it is unclear whether
obesity and diabetes are associated with breast cancer risk
in BRCA1 or BRCA2 mutation carriers. A recent
comprehensive study analysed the medical histories of
6052 women with BRCA1 or BRCA2 mutations, half of
whom developed breast cancer.61 There was no excess of
diabetes among patients with breast cancer in the period
before diagnosis, compared with control individuals
without cancer. However, there was a doubling in the risk
of diabetes among BRCA1 or BRCA2 mutation carriers in
Figure 2: Functional interactions between BRCA1, IGF-1, and ER signalling
Breast cancers in patients with BRCA1 mutations are more often ER negative
than tumours from non-carriers. Lack of ER in mutant BRCA1-associated
tumours might refl ect the fact that BRCA-associated breast cancers are usually
hormone indepenent. The BRCA1, IGF-1, and ER signalling pathways are tightly
interconnected, and feedback loops controlling the expression and action of
these hormonal networks in a coordinated fashion have been identifi ed.24,35,42,51–53
Dysregulated expression of single components of this complex regulatory
system might lead to amplifi ed pathological outcomes. E2=oestradiol.
IGF-1=insulin-like growth factor 1. ER=oestrogen receptor. IGF1R=IGF-1
www.thelancet.com/oncology Vol 13 December 2012 e541
the 15-year period after diagnosis of breast cancer
(compared with mutation carriers without breast cancer).
The risk was even higher for women with a body-mass
index higher than 25. Although the reason for this
increased diabetes risk is unknown, the researchers
postulated that the risk of diabetes might be associated
with weight gain after cancer therapy.
In terms of insulin eff ects, mutant BRCA1 has been
associated with increased lipogenesis due to relaxation of
the inhibitory action of wild-type BRCA1 on acetyl-CoA
carboxylase, a key enzyme in fatty acid synthesis.62
Additionally, BRCA mutation carriers seem to have
decreased blood IGFBP concentrations and sometimes
lack an allele containing cytosine–adenine repeats in the
IGF-1 promoter, which has been linked to decreased
insulin sensitivity.48 The association between metabolic
disorders, including diabetes and the metabolic syn-
drome, and BRCA1 and BRCA2 mutations warrants
Epigenetic control of BRCA1 and IGF1R
Although the studies discussed here provide evidence
of functional and physical interactions between the
BRCA1 and IGF1R pathways at transcriptional and post-
transcriptional levels, no studies so far have investigated
the eff ect of epigenetic events on joint regulation of
BRCA1 and IGF1R expression and action. DNA methy-
lation is a key epigenetic alteration aff ecting gene
expression. Methylation of CpG islands leads to inacti-
vation of transcription and has an important role in
development. Promoter CpG island methylation of
tumour suppressor genes is a classic hallmark of cancer
and aff ects most cellular pathways, including genes
involved in DNA repair and microRNAs. The relevance
of DNA methylation in cancer diagnosis and manage-
ment has been described. Developments in the area of
DNA methylation include the potential identifi cation of
molecular markers for early detection, the discovery of
epigenetic targets for therapy, and others.63
Several studies have examined possible methylation
of the BRCA1 promoter and the association between
BRCA1 methylation, gene expression, and cancer pheno-
type. For example, evaluation of the methylation status of
a 600-bp region of the human BRCA1 promoter, which
contains 30 CpG sites, established that these sites
were largely unmethylated in mammary epithelial cells,
peripheral blood lymphocytes, and several sporadic
breast-cancer cell lines.64 However, one sporadic cancer
cell line was roughly 60% methylated at all 30 CpG sites,
in association with a substantial decrease in BRCA1
mRNA compared with normal breast cells.64 An
additional study detected hypermethylation of the BRCA1
promoter in 51% of breast tumour biopsies, of which
67% did not express the protein.65 These results suggest
that hyper methylation could
inactivating mech anism for BRCA1 expression, either as
a fi rst or second hit. A recent clinical study examined the
be considered an
potential methylation of BRCA1 in peripheral blood cells
of patients with sporadic breast cancer; BRCA1 promoter
hypermethylation was more common in circulating cells
of patients with breast cancer than in healthy controls.66
Additionally, an association between BRCA1 methylation
and a specifi c SNP (ACA/ACA genotype at Thr594) in
ESR1 (oestrogen receptor gene), usually associated with
increased breast-cancer risk, was noted. Therefore,
analysis of BRCA1 methylation might provide relevant
Finally, bioinformatic analysis revealed the presence of
multiple CpG islands in the human IGF1R promoter.67
However, comprehensive analyses done in our laboratory
did not detect IGF1R methylation in a series of prostate
and endometrial cancer cell lines.67,68 Nevertheless,
methylation has an important role in control of IGF2.
Specifi cally, loss-of-imprinting of IGF2 leads to biallelic
expression of the gene, providing a proliferative
advantage to transformed cells by in creasing the
concentration of available IGF2 ligand.
MicroRNAs in regulation of BRCA1 and IGF1
MicroRNAs are short, non-coding RNAs that control
gene expression by targeting mRNAs and triggering
translation inhibition or degradation. Studies have
identifi ed several microRNAs that negatively control
expression of various components of the IGF1
signalling pathway, as well as BRCA1, BRCA2, and
Chang and colleagues70 showed that Arg1699Gln,
a moderate-risk variant of BRCA1, does not impair
DNA damage repair, but abrogates the repression of
microRNA-155, a putative oncomir (ie, a microRNA
associated with cancer). The investigators showed that
BRCA1 epigenetically represses microRNA-155 expres-
sion via its association with histone deacetylase 2,
which deacetylates histones H2A and H3 on the
microRNA-155 promoter. Furthermore, overexpression
Panel: BRCA1–IGF-1 interactions
• IGF1R variants are associated with breast-cancer risk
among BRCA1 or BRCA2 mutation carriers
• Risk of diabetes might be increased among patients with
BRCA1 or BRCA2 breast cancer
• IGF1R expression is higher in breast tumours from BRCA1
mutation carriers than in non-BRCA1 (sporadic) tumours
• Intratumoral IGF-1 concentrations are upregulated in
tumours from BRCA1 or BRCA2 mutation carriers
• Klotho, a candidate breast tumour suppressor, inhibits
activation of the IGF-1 pathway
• Hypermethylation is an inactivating mechanism for
• BRCA1 mutation status might aff ect IGF1R-directed
www.thelancet.com/oncology Vol 13 December 2012
of microRNA-155 accelerates the in-vivo growth of
tumour cell lines, whereas knockdown of microRNA-155
attenuates growth. This study emphasises the complex
(transcriptional, post-transcriptional, and epigenetic)
interplay between microRNAs and BRCA1, and suggests
that microRNA-155 is a potential therapeutic target for
BRCA1-defi cient tumours.
Can BRCA1 status predict response to IGF1R-
The IGF1 axis, and particularly IGF1R, have emerged
as promising therapeutic targets in oncology.13 Initial
phase 3 studies in unselected patients using monoclonal
antibodies against IGF1R have been disappointing,
highlighting the need to identify predictive biomarkers
that can identify potential responders.71 The eff ect of
selective IGF1R-targeted therapies according to BRCA1
or BRCA2 mutational status has not been rigorously
examined. Since BRCA1 exhibits a key role in DNA-
damage repair mechanisms elicited by exposure to
antitumour agents, the contribution of BRCA1 to
cisplatin sensitivity was examined in HCC1937 cells
(a BRCA1-null breast-cancer cell line) or BRCA1-
reconstituted HCC1937/BRCA1 breast cancer xenografts
in SCID mice.72 Cisplatin treatment induced almost
complete growth inhibition of BRCA1-defective xeno-
grafts, whereas BRCA1-reconstituted xenografts were
only partially inhibited. Cell-cycle analysis showed an
S and G2–M blockade in BRCA1-defective cells. Further-
more, gene arrays identifi ed perturbations of major
proliferation and survival pathways, including IGF1 and
ER. These results lend support to a recent study showing
that endometrial cancer cells with high IGF1R levels are
more likely to benefi t from an anti-IGF1R-directed
therapy than cells with reduced IGF1R levels.73
IGF1R has been identifi ed as a potent antiapoptotic,
prosurvival and, potentially, transforming receptor.
These attributes positioned IGF1R at a crucial location
on oncogenic maps. IGF1R has emerged as a promising
therapeutic target; however, we need to identify
biomarkers that can predict responsiveness to IGF1R-
Wild-type, but not mutant, BRCA1 can lead to
transcriptional suppression of IGF1R expression (with
ensuing reduction in IGF1R activation by circulating or
local IGF-1 or IGF-2). Loss-of-function mutation of BRCA1
in breast, ovarian, and other types of cancer might abolish
its tumour protective action, leading to constitutive
activation of the IGF1R signalling pathway. BRCA1
expression is also regulated by several cellular events,
including cell-cycle phase and ambient con centrations of
IGF-1. Data presented in this Review emphasise the
convergence of IGF1R-mediated cell survival, proliferative
pathways, and BRCA1-mediated tumour protective
pathways. Although these interactions have been mainly
characterised in familial cancers (because of the high
incidence of BRCA1 or BRCA2 mutations), it is clear that
IGF1R and BRCA1 might also be involved in sporadic
cancers. Elucidation of the complex interplay between
these signalling pathways at the transcriptional, post-
transcriptional, and epigenetic levels will enhance our
understanding of basic molecular oncology processes and
our ability to design and optimise cancer therapies.
Both authors designed the report, searched the literature, and wrote the
Confl icts of interest
We declare that we have no confl icts of interest.
HW’s laboratory is supported by grants from the US-Israel Binational
Science Foundation, Israel Science Foundation, Israel Cancer
Association, Insulin-Dependent Diabetes Trust (IDDT; UK), and Israel
Cancer Research Fund (ICRF; Montreal, Canada).
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Search strategy and selection criteria
We identifi ed data for this Review by a systematic search of
Medline with the terms “insulin-like growth factors”, “IGF-1”,
“IGF-2”, “IGF-1 receptor”, “BRCA1”, “BRCA2”, and “breast
cancer genes” for peer-reviewed basic and clinical studies.
The search was limited to reports written in English. Since the
BRCA1 gene was fi rst identifi ed in 1994, our search was
restricted to reports published between Jan 1, 1994, and
April 30, 2012. The fi nal reference list was selected on the
basis of originality and scientifi c and clinical relevance.
www.thelancet.com/oncology Vol 13 December 2012 e543
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