Stem cell therapy for hereditary breast cancer
In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for hereditary breast cancer therapies. Severalmolecular targeting therapies are described by activation and blocking distinct developmental signaling cascade elements, such as BRCA1, EG...
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| Опубліковано в: : | Цитология и генетика |
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Інститут клітинної біології та генетичної інженерії НАН України
2009
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| Цитувати: | Stem cell therapy for hereditary breast cancer / H. Rassi // Цитология и генетика. — 2009. — Т. 43, № 3. — С. 80-88. — Бібліогр.: 24 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859937917896491008 |
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| author | Rassi, H. |
| author_facet | Rassi, H. |
| citation_txt | Stem cell therapy for hereditary breast cancer / H. Rassi // Цитология и генетика. — 2009. — Т. 43, № 3. — С. 80-88. — Бібліогр.: 24 назв. — англ. |
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| description | In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for hereditary breast cancer therapies. Severalmolecular targeting therapies are described by activation and blocking distinct developmental signaling cascade elements, such as BRCA1, EGFR,hedgehog, Wnt/β catenin, and/or Notch pathways, which are frequently upregulated in cancer progenitor cells during the initiation and development of breast cancer.
В огляді наведено дані про недавні досягнення використання попередників зародкових, плідних та дорослих стовбурових клітин в терапії за допомогою молекулярного таргентинга шляхом активації та блокування сигнальних каскадних елементів, таких як BRCA1, EGFR, Wnt/β catenin и Notch pathways, які часто регулюються в попередниках ракових клітин під час ініціації та розвитку рака груді.
В настоящем исследовании сообщается о недавних достижениях использования предшественников зародышевых, плодных и взрослых стволовых клеток в терапии наследственного рака груди. Описаны варианты терапии с помощью молекулярного таргетинга путем активации и блокирования сигнальных каскадных элементов, таких как BRCA1, EGFR, hedgehog, Wnt/β catenin и Notch pathways, которые часто регулируются в предшественниках раковых клеток в ходе инициации и развития рака груди.
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Обзорные статьи
H. RASSI
National Medical Academy of Post�graduate Education Named
after P.L. Shupik Health ministry of Ukraine
E�mail: rasihussein@yahoo.com
STEM CELL THERAPY FOR
HEREDITARY BREAST CANCER
Both hereditary and sporadic breast cancers may develop
through dysregulation of self�renewal pathways of normal
mammary stem cells. Networks of proto�oncogenes and tumor
suppressors that control cancer cell proliferation also regulate
stem cell self�renewal and possibly stem cell aging. Breast
cancer susceptibility gene (BRCA1) is a nuclear phosphopro�
tein expressed in many nuclear processes, including stem cell
regulator, DNA damage repair, recombination, transcription,
ubiquitination, cell cycle checkpoint enforcement, and centro�
some regulation. In this study, we report on recent advances
on the functions of embryonic, fetal, and adult stem cell pro�
genitors for hereditary breast cancer therapies. Severalmolec�
ular targeting therapies are described by activation and block�
ing distinct developmental signaling cascade elements, such as
BRCA1, EGFR,hedgehog, Wnt/β�catenin, and/or Notch path�
ways, which are frequently upregulated in cancer progenitor
cells during the initiation and development of breast cancer.
Introduction
Breast cancer results from the dysregulation of
self�renewal pathways of normal mammary stem
cells. Both hereditary and sporadic breast cancers
may develop through deregulation of stem�cell self�
renewal pathways [1]. The hereditary breast cancer
(HBC) includes genetic alterations of various sus�
ceptibility genes such as TP53, ATM, PTEN or
MSH2, MLH1, PMS1, PMS2, CDH1, MSH3 and
MSH6, BRCA1 and BRCA2 [2]. Germline muta�
tions in BRCA1 and BRCA2 account for the major�
ity of families with multiple cases of breast and/or
ovarian cancer and also at least 10 % of cases below
the age of 40 years in Ukraine [3]. Most BRCA1 car�
cinomas have the basal�like phenotype and are
high�grade, highly proliferating, estrogen recep�
tor�negative and HER2�negative breast carcinomas,
characterized by the expression of basal markers
such as basal keratins, P�cadherin and epidermal
growth factor receptor [4, 5]. The BRCA1 carcino�
mas frequently carry p53 mutations. One of the
key functions of BRCA1 is to act as a stem cell reg�
ulator [6]. It regulates the development of the estro�
gen�receptor�negative stem cells into estrogen�
receptor�positive cells. When BRCA1 is missing,
genetically unstable stem cells accumulate and
then may develop into breast cancers. In this
review, we report on recent advances on the func�
tions of adult stem cells for hereditary breast can�
cer therapies.
Stem cells types in mammary gland
Stem cells are undifferentiated cells for which
the mitotic progeny have the potential to generate
differentiated cells throughout the lifespan. Self�
renewal and differentiation potential is the feature
of stem cells. However, distinct stem cell types
have been established from embryos and identified
in the fetal tissues and umbilical cord blood
(UCB), as well as in many adult mammalian tis�
sues and organs, such as bone marrow (BM),
breast, brain, skin, eyes,heart, kidneys, lungs, gas�
trointestinal tract, pancreas, liver,ovaries, prostate,
and testis [7].
Embryonic stem cell lines (ES cell lines) are
cultures of cells derived from the epiblast tissue of
the inner cell mass (ICM) of a blastocyst or earlier
morula stage embryos (Figure). A blastocyst is an
early stage embryo�approximately four to five days
old in humans and consisting of 50–150 cells. ES
cells are pluripotent and give rise during develop�
ment to all derivatives of the three primary germ
ISSN 0564–3783. Цитология и генетика. 2009. № 380
© H. RASSI, 2009
layers: ectoderm, endoderm and mesoderm. A
human embryonic stem cell is also defined by the
presence of several transcription factors and cell
surface proteins. The transcription factors Oct�4,
Nanog, and SOX2 form the core regulatory net�
work that ensures the suppression of genes that
lead to differentiation and the maintenance of
pluripotency [8]. The cell surface antigens most
commonly used to identify hES cells are the gly�
colipids SSEA3 and SSEA4 and the keratan sul�
fate antigens Tra�1–60 and Tra�1–81. Adult stem
cells are undifferentiated cells found throughout
the body after embryonic development that divide
to replenish dying cells and regenerate damaged
tissues. Most adult stem cells are lineage�restricted
(multipotent) and are generally referred to by their
tissue origin (mesenchymal stem cell, adiposede�
rived stem cell, endothelial stem cell, etc.) (Figu�
re). The pluripotent adult stem cells are rare and
generally small in number but can be found in a
number of tissues including mammary glands
[6–8]. A great deal of adult stem cell research has
focused on clarifying their capacity to divide or
self�renew indefinitely and their differentiation
potential. The use of adult stem cells in research
and therapy is not as controversial as embryonic
stem cells, because the production of adult stem
cells does not require the destruction of an embryo.
Additionally, because in some instances adult stem
cells can be obtained from the intended recipient,
(an autograft) the risk of rejection is essentially
non�existent in these situations.
Cancer stem cells originate from the transfor�
mation of normal epithelial stem cells in mamma�
ry gland. Cancer stem cells may provide targets for
the development of cancer prevention strategies.
Furthermore, because breast cancer stem cells may
be highly resistant to radiation and chemotherapy,
the development of more effective therapies for this
disease may require the effective targeting of this
cell population.
Mammary gland is a dynamic organ that under�
goes significant developmental changes during preg�
nancy, lactation, and involution. In the neonate,
Mammary gland development is not complete, con�
sisting only of a limited network of ducts. More
specifically, the postnatal growth of the mammary
gland during puberty, pregnancy, and lactationmight
notably be induced by estrogenic hormones that may
regulate epithelial stem cell behavior in paracrine
fashion. In this matter, the human adult mammary
gland adopts a lubulo�alveolarstructure that is com�
posed of different epithelial cell types, including
alveolar epithelial cells, contractile myoepithelial
cells forming the basal layer of ducts and alveoli, and
specialized epithelial cells constituting the luminal
layer of ducts. Distinct undifferentiated and multi�
potent stem cell subpopulations havebeen identified
in the mammalian mammary epithelium within the
niches localized near the basement membrane [8].
These stem cell subtypes, which can express either
estrogen receptor�α (ER�α�positive cells) or unde�
tectable ER�α levels (ER�α�negative cells), as well as
specific stem cell markers, including Sca�1, K19,
and Msi�1, are able to give rise to myoepithelialand
luminal epithelial cells in vitro [1]. Moreover, it has
also been shown that the propagation of human
undifferentiated mammary epithelial cells derived
from the reduction mammoplasties under the form
of nonadherent mammospheres in vitro, results in
the generation of three mammary epithelial cell
types [6].
These undifferentiated mammary epithelial cells
may generate a functional ductal�alveolar structure
resembling the mammary tree in reconstituted
three�dimensional Matrigel culture system [7]. In
addition, it has been observed that a suprabasal�
derived mammary epithelialcell line, which was able
to self�renew and differentiate into myoepithelial
and luminal epithelial cells, could also formterminal
duct lobular unit�like structures within a reconstitut�
edbasement membrane [8].
ІSSN 0564–3783. Цитология и генетика. 2009. № 3 81
Stem cell therary for hereditary breast cancer
Pluripotent, embryonic stem cells originate as inner mass
cells within a blastocyst
Role of estrogen and BRCA1 gene
in hereditary breast cancer
Breast cancer susceptibility gene (BRCA1) is a
nuclear phosphoprotein expressed in many nuclear
processes, including DNA damage repair, recom�
bination, transcription, ubiquitination, cell cycle
checkpoint enforcement, and centrosome regula�
tion [9]. The BRCA1 is mutated in about one half
of all hereditary breast cancer cases, and its expres�
sion is frequently decreased in sporadic cancers
[2]. Women with hereditary breast and ovarian can�
cer due to BRCA1 mutations are born with a muta�
tion in one BRCA1 allele, but only develop cancer
after mutation or allelic loss of the other
BRCA1 allele. Thus, this is in contrast to inherited
germline diseases, in which the genetic defect is
present in all cells. Breast cancers arising in carri�
ers of germline BRCA1 mutations frequently have a
basal�like phenotype [4, 5, 9]. Basal�like cancers
are characterized by high histological grade, cen�
tral necrotic areas, foci with metaplastic differenti�
ation, lack of ER and PR and HER2 (ErbB2)
expression, and consistent positivity for basal mark�
ers, including CK5/6, CK14, and EGFR.
Estrogen exposure is considered a significant
risk factor for breast cancer development. Estrogen
receptor (ER) alpha is expressed at low levels in
normal epithelia, and its expression is dramatical�
ly up�regulated as transformation progresses dur�
ing mammary hyperplasia and adenocarcinoma
development [3]. About 70 % of breast cancers
express ER and are estrogen�dependent for
growth. The BRCA1 inhibits signaling by the lig�
and�activated ER through the estrogen�responsive
enhancer element and block the transcriptional
activation function AF�2 of ER�alpha. In other
hand, BRCA1 suppresses estrogen�dependent
transcriptional pathways related to mammary
epithelial cell proliferation and that loss of this
ability contributes to tumorigenesis. This gene reg�
ulates Akt signaling and the PI3K/Akt pathway
modulates the ability of BRCA1 to repress ER�
alpha, in part through serine phosphorylation
events in the activation function�1 domain of ER�
alpha [1, 3, 10].
Regulation of stem cells
Networks of proto�oncogenes and tumor sup�
pressors that control cancer cell proliferation also
regulate stem cell self�renewal and possibly stem
cell aging [3]. Proto�oncogenes promote regener�
ative capacity by promoting stem cell function but
must be balanced with tumor suppressor activity to
avoid neoplastic proliferation. Conversely, tumor
suppressors inhibit regenerative capacity by pro�
moting cell death or senescence in stem cells. The
regulation of the self�renewal, differentiation, and
migration of mammary stem cells and their pro�
genitors that are localized in the mammary glands
appears to be assumed throughdistinct developmen�
tal signaling pathways such as hormones, EGF,
hedgehog, Wnt/β�catenin, Notch, and Bmi�1 [1].
The hedgehog signaling components PTCH1,
Gli1, and Gli2 are highly expressed in normal
human mammary stem/progenitor cells cultured as
mammospheres and that these genes are down�
regulated when cells are induced to differentiate.
Activation of hedgehog signaling increases mam�
mosphere�initiating cell number and mammosphere
size, whereas inhibition of the pathway results in a
reduction of these effects [6]. These effects are medi�
ated by the polycomb gene Bmi�1. Furthermore,
there is strong evidence suggesting that aberrant
activation of Wnt signaling induces mammary
tumors from stem/progenitor cells, and that Wnt
exerts its oncogenic effects through LRP5/6�
mediated activation of beta�catenin and mTOR
pathways. Inactivation of Notch signaling may con�
tribute to mammary carcinogenesis by deregulat�
ing the self�renewal of normal mammary stem
cells. Polycomb family proto�oncogene, Bmi�1, is
consistently required for the self�renewal of diverse
adult stem cells, as well as for the proliferation of
cancer cells in the same tissues. The Bmi�1 pro�
motes stem cell self�renewal partly by repressing
the expression of Ink4a and Arf, tumor suppressor
genes that are commonly deleted in cancer. Despite
ongoing Bmi�1 expression, Ink4a expression in�
creases with age, potentially reducing stem cell fre�
quency and function [7, 8]. Increased tumor sup�
pressor activity during aging therefore may partly
account for age�related declines in stem cell func�
tion. The studies demonstrated that BRCA1 plays a
critical role in the differentiation of ER�negative
stem/progenitor cells to ER�positive luminal cells.
Defect of BRCA1 gene may result in the accumula�
tion of genetically unstable breast stem cells, pro�
viding prime targets for further carcinogenic
events, because BRCA1 also plays a role in DNA
repair. Knockdown of BRCA1 in primary breast
ISSN 0564–3783. Цитология и генетика. 2009. № 382
H. Rassi
epithelial cells leads to an increase in cells display�
ing the stem/progenitor cell marker ALDH1 and a
decrease in cells expressing luminal epithelial mark�
ers and estrogen receptor [1, 6–8]. Thus, networks
of proto�oncogenes and tumor suppressors have
evolved to coordinately regulate stem cell function
throughout life. Imbalances within such networks
cause cancer or premature declines in stem cell
activity that resemble accelerated aging and breast
cancer.
Production of patient�specific
pluripotent stem cells
The generation of patient�specific pluripotent
stem cells has the potential to accelerate the imple�
mentation of stem cells for clinical treatment of
breast cancer. Induced pluripotent stem (iPS) cells
have recently been established by transfecting mouse
and human fibroblasts with the transcription fac�
tors Oct3/4 (Pouf51), Sox2, Klf4 and c�Myc,
known to be expressed at high levels in embryonic
stem (ES) cells [11]. Transfection is typically
achieved through viral vectors, such as retrovirus�
es. After 3–4 weeks, small numbers of transfected
cells begin to become morphologically and bio�
chemically similar to pluripotent stem cells, and
are typically isolated through morphological selec�
tion, doubling time, or through a reporter gene
and antibiotic selection. The iPS cells are believed
to be identical to natural pluripotent stem cells,
such as embryonic stem cells in many respects,
such as the expression of certain stem cell genes
and proteins, chromatin methylation patterns, dou�
bling time, embryoid body formation, teratoma
formation, viable chimera formation, and potency
and differentiability, but the full extent of their
relation to natural pluripotent stem cells is still
being assessed. These cells were first produced in
2006 from mouse cells and in 2007 from human
cells [12, 13]. Four key pluripotency genes essen�
tial for the production of pluripotent stem cells
were isolated; Oct�3/4, SOX2, c�Myc, and Klf4.
Cells were isolated by antibiotic selection for
Fbx15+ cells. However, this iPS line showed DNA
methylation errors compared to original patterns
in ESC lines and failed to produce viable chimeras
if injected into developing embryos. Using Nanog
which is an important gene in ESCs, DNA methy�
lation patterns and producing viable chimeras (and
thereby contributing to subsequent germ�line pro�
duction) indicated that Nanog is a major determi�
nant of cellular pluripotency. Unfortunately, one
of the four genes used (namely, c�Myc) is onco�
genic, and 20 % of the chimeric mice developed
cancer. In a later study, Yamanaka reported that
one can create iPSCs even without c�Myc. The
process takes longer and is not as efficient, but the
resulting chimeras didn’t develop cancer [11]. With
the same principle used earlier in mouse models,
Yamanaka had successfully transformed human
fibroblasts into human pluripotent stem cells using
the same four pivotal genes: Oct3/4, Sox2, Klf4,
and c�Myc with a retroviral system. Thomson and
colleagues used OCT4, SOX2, NANOG, and a
different gene LIN28 using a lentiviral system.
The viral transfection systems used insert the genes
at random locations in the host’s genome; this is a
concern for potential therapeutic applications of
these iPSCs, because the created cells might be
susceptible to cancer. Members of both teams con�
sider it therefore necessary to develop new delivery
methods [12].
The generation of iPS cells is crucial on the genes
used for the induction. The Oct�3/4 and certain
members of the Sox gene family (Sox1, Sox2, Sox3,
and Sox15) have been identified as crucial tran�
scriptional regulators involved in the induction
process whose absence makes induction impossi�
ble. Additional genes, however, including certain
members of the Klf family (Klf1, Klf2, Klf4, and
Klf5), the Myc family (C�myc, L�myc, and N�myc),
Nanog, and LIN28, have been identified to increase
the induction efficiency [13, 14].
Stem cell�based therapy
Embryonic, fetal, amniotic, umbilical cord blood
and adult stem cells could be used for treating
numerous genetic and degenerative disorders.
Among them, age�related functional defects, can�
cers, Parkinson’s and Alzheimer’s diseases, hema�
topoietic and immune system disorders, heart fail�
ures, chronic liver injuries, diabetes, arthritis, and
muscular, skin, lung, eye, and digestive disorders
as well as aggressive and recurrent cancers could be
successfully treated by stem cell�based therapies.
Clinical transplantation procedures for stem cells,
which depend on patient state and diagnosis, gener�
allyinvolve the i.v. injection or subcutaneous admin�
istration of a specific number of stem cells directly
into therapeutically targeted areas. In addition, the
ІSSN 0564–3783. Цитология и генетика. 2009. № 3 83
Stem cell therary for hereditary breast cancer
high plasticity and migratory potential of BM stem
cells also offer the possibility of mobilizing themin
vivo or injecting these stem cell types in circulation
to regenerate the particular functional progenitors
for the tissue regeneration [15]. Moreover, gene�
basedstrategies involving modifications or replace�
ment of a particular gene product, such as MDR1,
in stem cells and their more differentiated progen�
itors before their transplantation might now be
conceivedfor the treatment of cancer[16]. Nuclear
transfer, in which the nucleus from donor somatic
cells is transferred into an enucleated oocyte to
obtain the pluripotent embryonic stem cells, offers
another alternative source for the derivation of
primitive stem cells for cell replacement therapy
when no donor organ is available for transplanta�
tion [13]. However, molecular targeting of tumori�
genic cascade elements in tissue�specific cancer
progenitorcells, which are derived from the malig�
nant transformation of adult stem cells, also repre�
sents a novel approach for the treatment of diverse
metastatic and incurable cancer types by combina�
tion therapies [14].
The cancer stem cells play a critical role in both
initiation and relapse of the cancers as they are
resistant to the most of cytotoxic agents and able to
proliferate indefinitely. Several resistance mecha�
nisms have been proposed, including amplified
checkpoint activation and DNA damage repair as
well as increased Wnt/beta�catenin and Notch sig�
naling [7, 8]. Moreover, several studies have been
carried out with a variety of cancer cell line types
and on different animal models to identify new
therapeutic targets to block the growth and/or sur�
vival of the cancer cells. Among them, the molec�
ular targeting of distinct oncogenic signaling ele�
ments, which are activated in the cancer cells dur�
ing the progression of numerous cancer, represents
a promising strategy for the development of new
chemopreventive treatments and combination ther�
apies against some aggressive and metastatic can�
cers. Inactivation and/or activition of diverse hor�
mones, growth factors, cytokines and chemokines
(androgens, estrogens, EGF and TGF�α/EGFR,
IGF/IGFR, SHH/SMO, Wnt/β�catenin, Notch,
TGF�β, and SDF�1/CXCR4), and tumorigenic
signalingelements (telomerase, phosphatidylinosi�
tol 3�kinase [PI3K]/Akt,NF�κB, and Myc�1) may
contribute to the sustained growth and survival of
stem cells, as well as their malignant transforma�
tion during the initiation and cancer progression
[15, 16]. Therefore, their molecular targeting is of
importance to the elimination of cancer progenitor
cells, thereby inducing a complete tumor regres�
sion and cancer remission. There is described a
brief description of new therapeutic drugs that are
able to block the specific growth factor signaling
cascades that are frequently deregulated in the
stem cell�derivedcancer progenitor cells, as well as
the advantages that are associated with the use of
high�dose chemotherapy (HDCT) withhematopoi�
etic cell support.
Growth Factor Signaling Inhibitors
EGFR Family Member Inhibitors. Inactivation
of EGFR (erbB2) might represent a potent strate�
gy, alone or in combination with other conven�
tional treatments for numerous aggressive cancer
forms [17–19]. Among the selective agents target�
ing EGFR signaling, there are antibodies or anti�
sense oligonucleotides directed against EGFR or
its ligands EGF and TGF�, anti�ErbB2 antibody
trastuzumab (Herceptin) and the selective EGFR
tyrosine kinase inhibitors such as AG1478, gefi�
tinib and erlotinib [17]. These agents may induce
the inhibition of the growth, invasiveness, and
apoptotic death of diverse cancer cell types by
counteracting distinct mitotic cascades, including
MAPK, PI3K/Akt, NF�κB, phospholipase Cγ,
and Shc [19].
Hedgehog, Wnt/β�catenin, and Notch Signaling
Inhibitors. The inactivation of hedgehog signaling
by using either SMO signaling element inhibitor,
cyclopamine alkaloid, or the anti�SHH antibody
has been observed to result in vitro and in vivo in a
growth inhibition and the apoptotic death of the
metastatic cancer cells, whereas normal cells were
insensitive to the cytotoxic effects of these agents
[17]. In addition, molecular targeting of the
canonical Wnt/β�catenin signaling elements con�
stitutes another anticarcinogenic strategy for the
treatment of breast cancer [20]. The Wnt protein
inhibitors (such as Wnt�inhibitory factor�1), or
repressors disrupting nuclear lymphocyte
enhancer factor/T�cell factor/β�catenin complex�
es might counteract the intracellular and nuclear
accumulation of β�catenin, thereby inhibiting the
proliferation of cancer cells that is induced
through the Wnt/β�catenin pathway. Similarly, the
inhibition of the Notch signaling cascade, which
ISSN 0564–3783. Цитология и генетика. 2009. № 384
H. Rassi
also appears to participate in developing certain
cancer types, including acute T�cell lymphoblastic
leukemia and lymphoma, medulloblastoma, and
mucoepidermoid, colorectal, pancreatic, mam�
mary, ovarian, and lung carcinomas, may also rep�
resent another targeting approach in the therapeu�
tic interventions against these hyperproliferative
disorders [21]. For instance, the inhibition of the
β� and γ�secretases,whose proteases can cleave the
intracellular domain of the Notch transmembrane
receptor, thereby permitting its translocation into
the nucleus, where it participates in the transcrip�
tional activation of genes, may notably represent a
potent therapeutictarget for these malignant disor�
ders [17, 18].
BRCA1 gene therapy. Although BRCA1 is only
mutated in a small percentage of breast or ovarian
cancers, the majority of sporadic breast and ovarian
cancers appear to express low levels of BRCA1 mes�
senger RNA and protein. This appears to be a con�
sequence of loss of heterozygosity and promoter
methylation of the remaining BRCA1 allele. This
finding is important because it indicates that
restoration of normal «wild�type» BRCA1 expression
levels in many sporadic cancers may inhibit tumors
by a «genetic correction» strategy, wherein the loss
of BRCA1 expression contributes to tumorigenesis.
These results constitute the scientific basis for test�
ing BRCA1 gene therapy in patients with sporadic
breast, ovarian, and prostate cancers that lack spe�
cific point mutations in the BRCA1 gene [1–5].
Many approaches that use viral and nonviral
delivery systems have been employed to introduce
genes into tumor cells, thus changing their malig�
nant phenotype. Several different BRCA1 viral
vectors have been constructed and tested for effi�
cacy in preclinical xenograft models of breast and
ovarian cancer. Initial studies of a BRCA1 retrovi�
ral vector employed a complementary DNA that
encoded a splice variant vector that eliminates the
first 71 amino acids of the human protein, termed
BRCA1sv [22]. Studies of both growth inhibition
and DNA repair do not identify cellular or molecu�
lar differences between BRCA1sv and BRCA1 com�
plementary DNAs [23]. Intaperitoneal injection of
either BRCA1sv or a full�length BRCA1 retroviral
vector into ovarian cancer or breast cancer
xenografts in nude mice produces tumor inhibi�
tion. These studies show that treatment of estab�
lished SKOV3 or PA�1 ovarian cancer nude mice
xenografts with either the full�length or the splice
variant BRCA1 retroviral vector results in tumor
suppression. Necropsies showed that PA�1 tumor�
bearing mice treated with control media or low�
dose LXSN�BRCA1sv died with large intra�
abdominal tumors and ascites, whereas mice with
high�dose LXSN�BRCA1sv treatments died of lung
metastasis with significantly smaller abdominal
tumor [6–9, 23, 24]. The published phase 1 trial of
BRCA1sv retroviral gene therapy demonstrated gene
transfer and expression of the intraperitoneally
injected LXSN�BRCA1sv vector. The vector was
moderately stable in the peritoneum of these
patients, and antibody formation was rare. The
phase 2 trial performed in a group of patients with
lower tumor burdens [22], however, demonstrated
that tumor size and immune status strongly influ�
ence patient response to retroviral vectors, and
that vectors packaged in mouse cells are not suffi�
ciently stable to treat patients with small volume
intraperitoneal ovarian cancer.
Combination Therapies. The simultaneous inhi�
bition of diverse hormone and growth factor sig�
naling pathways, including BRCA1, ER, AR,
IGFR, EGFR, hedgehog, Wnt/β�catenin, Notch,
and/or G�protein�coupled receptors, as well as
VEGFR and PDGFR cascades, which can act in
cooperation by stimulating the growth, invasion,
and metastatic spread ofcancer cells at distant sites
during the different stages of cancer progression,
may also constitute more effective therapiesagainst
the aggressive and highly metastatic cancer forms
[15, 16]. As a matter of fact, some works have
revealed that complex cross�talks may occur
among the AR, ER�α/ER�β, EGFR/ErbB2 sig�
naling cascades in breast cancers [17, 18]. The
combination of the agents that are able to block
these tumorigenic pathways may be more effective
to treat these epithelial malignancies as a single
antihormonal therapy. Simultaneous blockade of
the EGFR and hedgehog pathways could represent
a more effective and safe therapeutic treatment
against certain metastatic cancerforms by decreas�
ing the secondary effects that are associated with
the use of high doses of these agents. Similarly, it
has been reported that the activation of EGFR
might lead to the cellular accumulation of β�
catenin, and Notch and EGFR signaling may
cooperate for the sustained growth and invasion of
certain cancer cell types [19, 20].
ІSSN 0564–3783. Цитология и генетика. 2009. № 3 85
Stem cell therary for hereditary breast cancer
Since the metastatic spread of diverse tumor
cells, including those from glioblastomas, melano�
mas, and pancreas, breast, and prostate cancers to
other specific tissues/organs, such as lymphnodes,
bone, lungs, and/or liver, appears to be governed
by the expression of diverse angiogenic factors,
such as VEGF�VEGFR system, matrix metallo�
proteinases, urokinase�type plasminogen activator
(uPA), cyclooxygenase�2 (COX�2), chemokines,
and surface adhesion molecules, their molecular
targeting may also constituteanother adjuvant can�
cer therapy [15]. In this matter, the specific block�
ade of the SDF�1�CXCR4 axis by using a specific
anti�SDF�1 antibody, anti�CXCR4 antibody, or
CXCR4 antagonist (TC14012, TN14003, or
AMD3100) has notably been observed to prevent
the metastatic spread and interfere with the hom�
ing of breast and prostate cancer epithelial cells at
their target metastatic sites, including lymph
nodes, bone, and lungs [16]. The results from pre�
clinical studies have also indicated that the use of
the EGFR inhibitors in combination with COX�
2 inhibitor or photodynamic treatment or as chemo�
and radiosensitizers resulted in more effective
chemopreventiveand curative treatments for patients
with advanced and metastaticcancer forms [17]. It
is noteworthy that the sequence of treatment with
the EGFR inhibitor and chemotherapy appears to
be a critical factor that should be considered for
clinical application. In contrast, the treatment of
cells with the EGFR inhibitor before chemothera�
py induced an antagonistic effect instead. In addi�
tion, since the resistance of several metastatic can�
cer cells to radiotherapy and chemotherapy has
been associated with the aberrant response ele�
ments in ceramide and caspase cascades, targeting
these apoptotic pathways also may represent another
antitumoral strategy [18]. Altogether, these recent
studies have indicated that molecular targeting of
EGFR signaling, alone or in combination with
other cytotoxic agents, may constitute a putative
strategy for conceiving more effective clinical treat�
ments against a variety of aggressive cancers [19].
High�Dose Cancer Therapy Plus HSCs. Stem cell
transplantation may also constitute an option as
adjuvant therapy for cancer, particularly in the
patients receiving high doses of chemotherapeutic
agents and/or radiation that, alongwith killing can�
cer cells, cause the severe damage to normaltissues
and/or destroy the hematopoietic cells. Thus, the
stemcell transplants might replace the endogenous
stem cells destroyed by high�dose cancer treat�
ment, thereby producing healthy hematopoietic
cell lineages and improving the immune system
defense. The autologous or allogeneic transplanta�
tion of UCB, BM, or MPB stem cells and their
progenitors might be effectuated in combination
with HDCT for numerous aggressive cancer forms
to replace BM and blood�forming cells that have
been destroyed by chemotherapy. AML and high�
grade lymphoma are among the principal types of
cancer that are usually treated with hematopoietic
cell support as adjuvant therapy [16]. The different
subtypes of AML appear to result from distinct
mutations at the level of HSCs, the appearance of
which may give rise to primitive leukemic stem
cells (LSCs) possessing a specific phenotype, such
as CD90–,CD117–, and CD123+ [24]. These malig�
nant LSCs, which are able to self�renew, might
generate a heterogeneous AML cell population,
thereby maintaining leukemic blasts [17]. Interes�
tingly, it has been proposed that the maintenance
of LSCs in quiescent status might contribute to
their survival after chemotherapeutic treatment
and leukemia relapse. Hence, the selective apop�
tosis of LSCs by using agents such as proteasome
inhibitor MG�132 may constitute an adjuvant
treatment for AML [18].
In addition, transplantation or mobilization of
HSCs and their progenitors in systemic circulation
is often used as immune support in combination
with HDCT for the treatment of patients with cer�
tain highly aggressive solid tumors, and more partic�
ularly in advanced and metastatic stages of germi�
nal cell tumors, retinoblastoma, myeloma, brain,
lung, kidney, breast, and ovarian cancers [24].
However, the timing of the injection of HSCs dur�
ing the disease and the number of grafted cells are
among the major factors influencing the success of
the engraftment and/or survival of patients. In this
matter, the in vivo eliminationof circulating tumor
cells by purging prior to treatment may decrease
the cancer progression in high�risk patients.
Moreover, the ex vivo expansion of HSCs or the
mobilization of HSCs from BM into the peripher�
al blood by using mobilizingagents such as G�CSF
and AMD3100 might also lead to a great number
of stem cells and their progenitors in bloodstream,
thereby decreasing the recovery time after HDCT.
The differentiated HSC�derived progenitors, such
ISSN 0564–3783. Цитология и генетика. 2009. № 386
H. Rassi
as dendritic cells, which are among the most effi�
cient cells of the immune system in presenting an
antigen to helper/cytotoxic T lymphocytes, might
also to be used as an adjuvant treatment in cancer
immunotherapy to eliminate the neoplastic cells
that express immunogenic antigens at their sur�
face. Furthermore, UCB also contains a substan�
tial amount of CD16–/CD56+ natural killer cells
that might be expanded in the presence of IL�12 or
IL�15 and that show a high rate of proliferation
and cytotoxic effects against some cancers, partic�
ularly leukemia. In addition, the chemoprotection
against myelotoxicity induced by HDCT may also
be counteracted by genetic manipulations in HSCs
conferringto their progenitors resistance to certain
cytotoxic effectsof drugs, such as the expression of
MDR1 [16, 17].
Conclusion
These recent works in the field of stem cell biol�
ogy have identified intrinsic mitogenic signaling
cascades that are activated in mammary embryon�
ic, fetal, and adult stem cells during the normal
process of self�renewal and differentiation. These
cellularevents may also be implicated in the regen�
erating process after mammary gland injuries.
Hence, this offers the possibility of differentiating
these stem cell types into the specific mature cell
lineages in vitro, ex vivo, and in vivo by using
appropriate growth factors and cytokines for their
use in basic research, as well as in transplantation
for breast cancer. Several molecular targeting ther�
apies may also be conceived by activation and
blocking distinct developmental signaling cascade
elements, such as BRCA1, EGFR, hedgehog,
Wnt/β�catenin, and/or Notch pathways, whichare
frequently upregulated in cancer progenitor cells
during the initiation and development of breast
cancer.
Х. Расси
ТЕРАПИЯ НАСЛЕДСТВЕННОГО РАКА ГРУДИ
С ПОМОЩЬЮ СТВОЛОВЫХ КЛЕТОК
Как наследственный, так и спонтанный рак груди
может развиваться из�за нарушения регуляции путей
самообновления нормальных стволовых клеток мо�
лочной железы. Совокупность протоонкогенов и суп�
рессоров опухолей, которые контролируют пролифе�
рацию раковых клеток, также регулирует самообнов�
ление стволовых клеток и, возможно, их старение. Ген
BRCA1 кодирует ядерный фосфопротеин, который
экспрессируется в целом ряде процессов, включая ре�
гуляцию стволовых клеток, репарацию повреждений
ДНК, рекомбинацию, транскрипцию, убихитиниро�
вание, усиление клеточного цикла и регуляцию цент�
росом. В настоящем исследовании сообщается о не�
давних достижениях использования предшественни�
ков зародышевых, плодных и взрослых стволовых
клеток в терапии наследственного рака груди. Описа�
ны варианты терапии с помощью молекулярного тар�
гетинга путем активации и блокирования сигнальных
каскадных элементов, таких как BRCA1, EGFR,
hedgehog, Wnt/β�catenin и Notch pathways, которые
часто регулируются в предшественниках раковых
клеток в ходе инициации и развития рака груди.
Х. Рассi
ТЕРАПІЯ УСПАДКОВАНОГО РАКУ ГРУДІ
З ДОПОМОГОЮ СТОВБУРОВИХ КЛІТИН
Як успадкований, так і спонтанний рак груді може
розвиватися через порушення регуляції шляхів само�
оновлення нормальних стовбурових клітин молочної
залози. Сукупність протоонкогенів та супресорів пух�
лин, які контролюють проліферацію ракових клітин,
також регулюють самооновлення стовбурових клітин
та, можливо, їх старіння. Ген BRCA1 кодує ядерний
фосфопротеїн, який експресується в ряді процесів,
включаючи регуляцію стовбурових клітин, репарацію
пошкоджень ДНК, рекомбінацію, транскрипцію,
убіхітинування, посилення клітинного циклу і регуля�
цію центросом. В огляді наведено дані про недавні
досягнення використання попередників зародкових,
плідних та дорослих стовбурових клітин в терапії за
допомогою молекулярного таргентинга шляхом акти�
вації та блокування сигнальних каскадних елементів,
таких як BRCA1, EGFR, Wnt/β�catenin и Notch path�
ways, які часто регулюються в попередниках ракових
клітин під час ініціації та розвитку рака груді.
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Received 23.07.08
ISSN 0564–3783. Цитология и генетика. 2009. № 388
H. Rassi
|
| id | nasplib_isofts_kiev_ua-123456789-66647 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0564-3783 |
| language | English |
| last_indexed | 2025-12-07T16:10:06Z |
| publishDate | 2009 |
| publisher | Інститут клітинної біології та генетичної інженерії НАН України |
| record_format | dspace |
| spelling | Rassi, H. 2014-07-19T18:38:49Z 2014-07-19T18:38:49Z 2009 Stem cell therapy for hereditary breast cancer / H. Rassi // Цитология и генетика. — 2009. — Т. 43, № 3. — С. 80-88. — Бібліогр.: 24 назв. — англ. 0564-3783 https://nasplib.isofts.kiev.ua/handle/123456789/66647 In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for hereditary breast cancer therapies. Severalmolecular targeting therapies are described by activation and blocking distinct developmental signaling cascade elements, such as BRCA1, EGFR,hedgehog, Wnt/β catenin, and/or Notch pathways, which are frequently upregulated in cancer progenitor cells during the initiation and development of breast cancer. В огляді наведено дані про недавні досягнення використання попередників зародкових, плідних та дорослих стовбурових клітин в терапії за допомогою молекулярного таргентинга шляхом активації та блокування сигнальних каскадних елементів, таких як BRCA1, EGFR, Wnt/β catenin и Notch pathways, які часто регулюються в попередниках ракових клітин під час ініціації та розвитку рака груді. В настоящем исследовании сообщается о недавних достижениях использования предшественников зародышевых, плодных и взрослых стволовых клеток в терапии наследственного рака груди. Описаны варианты терапии с помощью молекулярного таргетинга путем активации и блокирования сигнальных каскадных элементов, таких как BRCA1, EGFR, hedgehog, Wnt/β catenin и Notch pathways, которые часто регулируются в предшественниках раковых клеток в ходе инициации и развития рака груди. en Інститут клітинної біології та генетичної інженерії НАН України Цитология и генетика Обзорные статьи Stem cell therapy for hereditary breast cancer Терапія успадкованого раку груді з допомогою стовбурових клітин Терапия наследственного рака груди с помощью стволовых клеток Article published earlier |
| spellingShingle | Stem cell therapy for hereditary breast cancer Rassi, H. Обзорные статьи |
| title | Stem cell therapy for hereditary breast cancer |
| title_alt | Терапія успадкованого раку груді з допомогою стовбурових клітин Терапия наследственного рака груди с помощью стволовых клеток |
| title_full | Stem cell therapy for hereditary breast cancer |
| title_fullStr | Stem cell therapy for hereditary breast cancer |
| title_full_unstemmed | Stem cell therapy for hereditary breast cancer |
| title_short | Stem cell therapy for hereditary breast cancer |
| title_sort | stem cell therapy for hereditary breast cancer |
| topic | Обзорные статьи |
| topic_facet | Обзорные статьи |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/66647 |
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