Download Breast cancer risk in BRCA1 mutation carriers: insight from mouse

symposium article
Annals of Oncology 24 (Supplement 8): viii8–viii12, 2013
doi:10.1093/annonc/mdt305
Breast cancer risk in BRCA1 mutation carriers: insight
from mouse models
M. H. Barcellos-Hoff1* & D. L. Kleinberg2
Departments of 1Radiation Oncology, New York University School of Medicine, New York,; 2Medicine, New York University School of Medicine, New York, USA
symposium
article
Since its identification 20 years ago, the biological basis for the high breast cancer risk in women who have germline
BRCA1 mutations has been an area of intense study for three reasons. First, BRCA1 was the first gene shown to
associate with breast cancer risk, and therefore serves as model for understanding genetic susceptibility. Second, the
type of breast cancer that occurs in these women has specific features that have engendered new hypotheses about the
cancer biology. Third, it is hoped that understanding the origins of this disease may provide the means to prevent
disease. Resolving this question has proven extremely challenging because the biology controlled by BRCA1 is complex.
Our working model is that the high frequency of basal-like breast cancer in BRCA1 mutation carriers is the result of a selfperpetuating triad of cellular phenotypes consisting of: (i) intrinsic defects in DNA repair and centrosome regulation that
lead to genomic instability and increases spontaneous transformation; (ii) aberrant lineage commitment; and (iii) increased
proliferation due to in large part to increased IGF-1 activity. We propose that the last is key and is a potential entree for
preventing breast cancer in BRCA1 mutation carriers.
Key words: BRCA1, breast cancer, genomic instability, mammary gland, mouse models, stem cells
the biological consequences of BRCA1
germline mutations
The observation that Ashkenazi Jewish women preferentially
develop aggressive cancers early in life, led to identification of
BRCA1 gene and to new understanding of the biology of breast
cancer (reviewed herein and in [1]). Women carriers have up to
80% risk of developing breast cancer, as well as a 40% risk of
ovarian cancer. Moreover, cancers associated with BRCA1
mutations are frequently negative for estrogen receptor,
progesterone receptor, and HER2 amplification, so-called triplenegative breast cancers (TNBC), which is usually associated
with a very poor prognosis.
Prophylactic mastectomy specimens from BRCA1 mutation
carriers also have a high frequency of premalignant
histopathological lesions not detected by physical examination
or radiological assessment [2]. Gross cystic disease is also
associated with increased risk of breast cancer [3].
experimental models and phenotypes of
Brca1 mutation
The mammary glands of mice with Brca1 deficiency exhibit
different degrees of abnormal morphogenesis characterized by
blunted ductal morphogenesis (or in some models dilated
mammary ducts), hyperplastic alveolar nodules, and neoplasia
reviewed in [4]. Mice with homozygous mutations in the Brca1
*Correspondence to: Dr. M. H. Barcellos-Hoff, Department of Radiation Oncology, 566
First Avenue, New York, NY 10016, USA. Tel: +212-263-3021; E-mail: [email protected]
gene do not survive. To circumvent the problem, the Deng
laboratory excised exon 11, so-called Δ11, from the gene in the
mammary gland by MMTV-Cre [5]. Both Kim and Xu noted
the late development of carcinoma, but only in a small number
of animals. For that reason, the Deng laboratory bred Brca1
deficient animals with p53 deficient animals to produce enough
animals to study effects on cancer development that occurs
between 7 and 17 months of age.
Brca1 deficiency and genomic instability
Genomic instability, aneuploidy, and centrosome aberrations
are frequent early events in epithelial cancer [6–8]. BRCA1
functions to control DNA damage response [9] and centrosome
replication [10]. Constitutive activation of downstream signaling
pathways that endow epithelial cells with an increased rate of
proliferation also lead to spontaneous DNA damage and
genomic instability that promote a premalignant state [11, 12].
Breast cancers of BRCA1 mutations carriers have more
chromosomal abnormalities than sporadic breast cancers.
Similarly, mice deficient in full-length Brca1 have decreased
expression of genes that are involved in the spindle checkpoint
and have an impaired DNA damage response (reviewed in
[13]). Genomically unstable cells are most susceptible to
malignant transformation [14].
Approximately two-thirds of invasive breast cancers are
aneuploid. Numerical and structural centrosome abnormalities
are hallmarks of almost all solid tumors and centrosome
deregulation has been implicated in the rapid generation of
multipolar mitoses and chromosomal instability. Centrosome
size and centrosome number show a positive, linear correlation
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
Annals of Oncology
with aneuploidy and chromosomal instability in breast cancer
[7]. Centrosomes are small cellular organelles, which organize
the mitotic spindle during cell division but are also involved in
cell shape and polarity. Accurate control of centrosome
duplication is critical for symmetric mitotic spindle formation
and thereby contributes to the maintenance of genome
integrity. Centrosome aberrations can arise as a consequence of
abortive mitotic events that elicit a defective centrosome
checkpoint or centrosome aberrations can arise in normal,
diploid cells and precede genomic instability. Ionizing radiation
induces aberrant centrosomes, which may contribute to its
carcinogenic action, in part by affecting BRCA1 expression [15].
Moreover, the inherent asymmetry of centrosomes in which
duplication of mother centriole generates the daughter centriole
endows the two centrioles with different characteristics after cell
division. This inherent asymmetry of centrioles has been shown
to regulate the orientation of the mitotic spindle in which the
cell that retains the mother centriole is retained in the stem cell
niche whereas the other cell that receives the daughter centriole
moves away from the niche to differentiate [16]. As a
consequence, centrosome aberrations can promote
tumorigenesis by not only increasing aneuploidy but also
because spindle misalignment can compromise cell-fatedeterminant function during stem cell division and increasing
number of stem or progenitor cells.
Brca1 deficiency and mammary lineage
Dysregulated epithelial stem cell number itself is speculated to
promote tumorigenesis in a particular tissue [17, 18]. Lifetime
breast cancer risk correlates with factors that promote stem cell
proliferation [19]. In mouse models, genetic manipulation of
β-catenin transcriptional activity increases stem cells, reduces
tumor latency, and increases tumor display of progenitor cell
markers [20, 21], while increased symmetric division in the
Trp53 null mammary epithelium is thought to contribute to the
high rate of transformation [22]. One idea that underlies the
interest in stem cells is that DNA damage in stem cells can be
‘fixed’ by passing it on to daughter cells that then expand
further, each round of subsequent replication being the occasion
for more mistakes. This is countered by the primordial strand
hypothesis in which stem cells pass on the replicated strand of
DNA to daughters, retaining the unreplicated template in
pristine condition [23–25]. However, because stem cells must
not only be capable of producing many differentiated progeny,
but able to switch between self-renewal and differentiation when
appropriate, stem cell self-renewal can also be affected during
tissue regeneration after injury from carcinogen exposure [26].
Hence, an early increase in stem cell number may itself be a
factor in cancer development [27].
An example to illustrate the potential consequences of stem
cell deregulation comes from our studies of radiation
carcinogenesis [28]. We used a novel mammary chimera model
that consists of clearing the mammary gland of endogenous
parenchyma at 3 weeks of age, irradiating the mouse at 10
weeks, and transplanting the cleared mammary fat pads 3 days
later with syngeneic Trp53 null mammary fragments. The doses
(10–100 cGy) used in this study are epidemiologically associated
with increased breast cancer in women, and could be delivered
Volume 24 | Supplement 8 | November 2013
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as a result of repeated CT scans or as a result of radiotherapy
(depending on the site and mode of therapy). Breast carcinomas
from unirradiatedTrp53 null transplanted to hosts previously
irradiated occurred sooner and grew faster compared with
controls. Surprisingly, the predominant type of tumor shifted
from estrogen receptor (ER) positive to negative. Consistent
with the cell of origin hypothesis that ER-negative tumors arise
from stem or progenitor cells, expression profiling of tumors
from irradiated hosts also showed a strong signature of
mammary stem cells. Notably, a similar enrichment for the
mammary stem cell signature was found shortly after irradiation
of intact mammary gland. We hypothesized that the increase in
ER-negative tumors in irradiated mice was due to a radiationinduced expansion of mammary stem cells, which was
supported by functional assays of mammary stem cells and
activation of the Notch signaling pathway. Remarkably, this
mouse model recapitulates the biology of breast cancer
following radiation therapy for childhood cancers, in which
ER-negative tumors are significantly enriched [29]. Thus, an
exogenous event like radiation exposure that affects stem cell
self-renewal can prime the tissue to develop breast cancer of a
particular type.
A unique feature of the BRCA1 deficient breast is aberrant
lineage commitment. Several laboratories using different
approaches, including marker analysis, cell surface antigens, and
functional assays have documented altered epithelial lineage
commitment in both human tissue and mouse models [30–35].
The importance of this in breast cancer stems from the cell of
origin hypothesis, which was recently comprehensively reviewed
by Visvader [36]. This hypothesis poses that the heterogeneity
of breast cancer is determined by the cell of origin’s position
within the normal breast epithelial hierarchy and that upon
transformation its fundamental programming remains evident
in the biology, behavior, and signature of the cancer subtype
[36]. This hypothesis suggests that stem cells give rise to tumors
that are less differentiated, ER-negative and more aggressive,
such as the claudin-low and basal-like cancers, and that more
differentiated cells give rise to the ER-positive luminal types
[18, 37].
Basal-like breast cancers arising in women carrying
mutations in the BRCA1 gene are thought to develop from
mammary stem or progenitor cells [18, 37], but there has been
considerable debate as to which specific cell in the hierarchy is
the culprit. Knockdown of BRCA1 in primary breast epithelial
cells leads to an increase in cells displaying ALDH1, a stem cell
marker, and a decrease in cells expressing luminal epithelial
markers and ER [34]. In breast tissues, loss of heterozygosity for
BRCA1 was seen in ALDH1-positive lobules but not in adjacent
ALDH1-negative lobules, which suggests that the loss of BRCA1
function blocks epithelial lineage commitment of ER-positive
cells.
A study by Lindeman and colleagues [33, 38] identified a
luminal progenitor cell using surface markers and provided
evidence that suggests that these ER-negative cells are expanded
in BRCA1 mutation carriers. Cell surface marker analysis
showed that tissue heterozygous for a BRCA1 mutation
(BRCA1-mutant samples) contained substantially fewer cells in
the mammary stem cell enriched (basal) subset
(CD49fhiEpCAM–) but an increase in the luminal progenitor
doi:10.1093/annonc/mdt305 | viii
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cell fraction (CD49f + EpCAM + ) relative to age-matched
normal breast tissue [38].
In support of the luminal expansion, Smalley and colleagues
[32] have shown that Brca1 deletion in both basal and luminal
cells generate tumors with basal-like tumor profiles, but only
those from the luminal promoter have histological features
associated with BRCA1 mutation in women.
interplay between BRCA1 and IGF-1
Mammary development is mediated by the ovarian-pituitary
hormonal axis. Rodents have been used to define the critical
endocrine signals in mammary development (see [39]). While
estrogen (E2) alone stimulates mammary ductal morphogenesis,
the combination of estrogen together with progesterone causes
lobulo-alveolar development similar to that seen during
pregnancy. The pituitary gland is essential for mammary
development, as demonstrated by the absence of mammary
development in hypophysectomized animals, even if E2 is
administered in high concentration. Pituitary derived growth
hormone (GH), together with E2, is responsible for ductal
morphogenesis, while estrogen, progesterone, GH, and prolactin
interact to stimulate lobulo-alveolar development in preparation
for lactation. Studies in mice suggest that all known actions of
GH in mammary development are mediated by IGF-I. IGF-I
has been shown to substitute for GH in mammary development
in hypophysectomized animals [40, 41] and neither E2 nor GH
has any effect on ductal morphogenesis unless animals are also
treated with IGF-I. Indeed IGF-I alone was capable of
stimulating some degree of ductal branching in the complete
absence of GH, E2, and progesterone [41]. Increasing IGF-1
action in normal animals increases proliferation in mammary
glands together with greater phosphorylation of target proteins,
IGF-IR, ERK, and AKT.
As it is a necessary signal for epithelial proliferation, it is not
surprising that IGF-I also plays an important role in the
proliferation of early lesions and neoplastic malignancies [39].
We recently tested the idea that inhibiting IGF-1would be
effective in reducing aberrant proliferation, as shown for
tamoxifen. Pasireotide is a somatostatin analog that blocks IGFI action within the mammary gland and also lowers serum IGFI by inhibiting secretion of GH [42]. Female rats that are both
hypophysectomized and oophorectomized at 21 days develop
hyperplasia when treated for 7 days with high doses of human
GH and follicular phase levels of E2 [43]. Pasireotide was as
effective as tamoxifen in inhibiting proliferation and
hyperplasia.
Mutation or deficiency of BRCA1 leads to exaggerated
estrogen, progesterone, and IGF-I activity with a major effect on
increased cell proliferation. The BRCA1 gene inhibits ER
signaling in transfected cells [44], ER activity [45], and estrogen
inducible gene expression [46]. It also regulates progesterone
receptor signaling activity, and inhibits IGF-I action [47, 48]. All
of these are direct effects with E2 binding to ER and acting as a
co-repressor and BRCA1 binding to the IGF-IR promoter and
suppressing transcription of IGF-IR mRNA. Breast tumors from
BRCA1 mutation carriers have elevated IGF-IR and IGF-I levels
[49, 50]. BRCA1 also has important independent actions on
DNA damage response [51], stem and progenitor cell fate [34],
viii | Barcellos-Hoff and Kleinberg
Annals of Oncology
cell cycle regulation [52] and telomerase activity [53] among
others. Deficiency of the mRNA or protein disrupts these
functions.
BRCA1 deficiency also leads to increased expression of several
insulin-like growth factor 1 (IGF-1) signaling axis members in
multiple experimental systems, including mice, primary
mammary tumors, and cultured human cells [47, 48]. It also
causes increased E2 and progesterone activity [44, 46]. As IGF-I
is permissive for E2- and progesterone-induced proliferation,
blockade of IGF-I activity should, and does, inhibit its own
action and proliferation induced by E2 and progesterone.
Moreover, experimental models show that increasing IGF-1
activity or expressing a constitutively active receptor can itself
independently promote breast cancer [54].
Understanding that fundamental IGF-1 biology drives
proliferation in the mammary gland led to a trial in which a
somatostatin analog, octreotide, was used together with
tamoxifen for breast cancer prevention [55]. However, no
benefit was evident. Why? Not all somatostatin analogs have the
same action. Octreotide is a strong somatostatin receptor ligand
whose major action is reduction in circulating GH largely
through SSTR2. Pasireotide also lowers GH but it also has a
strong tissue-specific IGF-1 inhibitory action in the mammary
gland. Based on our animal data and the similar action of a IGF1 small molecule inhibitor, we believe that the primary action of
pasireotide in the mammary gland is IGF-1 inhibition [42].
chemoprevention in BRCA1 mutation
carriers
In women who have sporadic breast cancer, tamoxifen, and the
related raloxifene, target E2-mediated proliferation. There is
clear evidence of efficacy of prolonged treatment in certain
populations, but each has limitations. Raloxifene may be not be
applicable to premenopausal women, and tamoxifen has low
acceptance rates [56]. More importantly, these therapies only
target proliferation in response to ovarian hormone action [43],
yet breast cancer is clearly not just a disease of proliferation.
Genomic instability and aberrant lineage commitment in
BRCA1 mutation carriers are critical to the progression to
invasive cancer. As noted above, several studies have shown that
BRCA1 loss or mutation affects mammary lineage, which in
turn affects the rate and type of cancer that develops [18, 32–34,
38]. The experimentally demonstrable aberrant lineage
commitment or stem cell deregulation is thought to explain the
particular risk of triple-negative breast cancer. A feedforward
loop of increased activity of IGF-1 is a distinct contributor to
the heightened responsiveness to ovarian hormones, but
BRCA1 mutations can also autonomously increase proliferation.
Together, the concurrent phenotypes stemming from BRCA1
mutations interact in a more complex pathogenesis than the
sequential acquisition of genetic and epigenetic events in
sporadic cancer.
The increasingly more detailed documentation of these
phenotypes in both human tissue and novel mouse models give
credence to the contention that breast cancer is preventable in
this population. An ideal therapy would remove the germline
mutations but this is unlikely in the foreseeable future. BRCA1
Volume 24 | Supplement 8 | November 2013
Annals of Oncology
deficiency reduces DNA repair, increases genomic instability,
increases proliferation and skews the mammary lineage; thus
targeting any one, while leaving the others, could delay cancer,
which would certainly be a start. Finding a pharmacological
target requires new approaches. A novel proposal is to use PARP
inhibitors to selectively eliminate BRCA1 mutant cells that have
undergone loss of heterozygosity, based on the paradigm of
synthetic lethality [57].
The growing knowledge of BRCA1 biology has given rise to
several provocative questions. If the basis for cancer risk is due
to defective DNA repair, as is widely believed, why are not all
tissues at risk? If proliferation is necessary, why are not
antiestrogens effective in this setting? And if the cell of origin is
the defining factor for the increase in triple-negative breast
cancer, why is there such conflicting evidence experimentally?
Eradicating the risk of breast cancer in this population will
require defining and removing the lynchpin encoded by BRCA1
deficiency that promotes malignancy in this specific tissue.
funding
This research was supported by Department of Defense Breast
Cancer Research program (W81XWH-11-1-780 to MHBH and
W81XWH-11-1-779 to DLK).
disclosure
The authors have declared no conflicts of interest.
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