Tmp526a TMP

The
journal
of
oncopathology
Review Article
Transforming Growth Factor Beta (TGF-b),

Mesenchymal-Epithelial Transition (MET) and
Breast Cancer Metastasis
Binnaz Hatice Mirac Demirkan, Prof.
Abstract
From the Division of Medical Oncology,
Department of Internal Medicine, Faculty of
Medicine, Dokuz Eylul University, Izmir,
Turkey (B.H.M.D.). Correspondence: Binnaz
Hatice Mirac Demirkan, Division of Medical
Oncology, Department of Internal Medicine,
Faculty of Medicine, Dokuz Eylul University,
35340 Izmir, TURKEY (demirkan.binnaz@
yahoo.com).
Conception and design: Binnaz Hatice Mirac
Demirkan
Collection and assembly of data: Binnaz
Hatice Mirac Demirkan
Data analysis and interpretation: Binnaz
Hatice Mirac Demirkan
Manuscript writing: Binnaz Hatice Mirac
Demirkan
Final approval of manuscript: Binnaz Hatice
Mirac Demirkan
Submitted August 17, 2014; accepted August
28, 2014
TJOP 2014;2:7789
DOI: 10.13032/tjop.2052-5931.100112.
Copyright # 2014 Optimal Clinical (Doctors.MD).
Genetic and microenviromental factors model the tissue architecture. The advance
of gene expression profiling and individual tumor characterizing analysis have
enabled to identify the clinical significance of transforming growth factor beta
(TGF-b), epithelial-mesenchymal transition (EMT), and mesenchymal-epithelial
transition (MET) signaling pathways for metastatic process. TGF-b, a potent
multifunctional (both physiologic and pathophysiologic) regulatory polypeptide,
has been extensively studied in relation to malignancy. According to alterations in
the composition of surrounding extracellular matrix (ECM), normal and cancer
cells respond differently to TGF-b/TGF-b signaling pathways. The progressive
research in understanding the mechanisms controlling epithelial plasticity (EMTMET) in the mammary gland can enable to identify targets for therapy and
biomarkers for prognosis and prediction of treatment outcome for breast cancer
patients. Therapeutic targets for TGF-b and MET signaling pathways are in early
phase clinical trials in several tumor types including mammary tumors. The review
includes recent advances in these paradox pathways and their clinical implications
for breast cancer.
Keywords: transforming growth factor beta (TGF-b); mesenchymal-epithelial
transition (MET); mesenchymal-epithelial transition factor (c-MET); breast cancer;
metastasis; treatment
ransforming growth factor beta (TGF-b), a potent multifunctional regulatory

polypeptide and a prototypical member of a large family of cytokines, does
not only have physiologic functions such as embryonic development, tissue
repair, wound healing, and immune response, but has pathophysiologic functions
like acting as both a tumor suppressor and a tumor promoter in cancer biology as
well.13 It can suppress tumor growth in the early stages of tumor development,
whereas it can promote tumor growth in the later stage.4,5 TGF-b is always
produced as an inactive cytokine that cannot bind to its receptor and function
unless the latent complex is activated. Many mechanisms such as avb6 integrin,
calpain, cathepsin D, chymase, elastase, endoglycosidase F, kallikrein, matrix
metalloproteinase 9 (MMP-9), neuraminidase, plasmin, thrombospondin-1 (TSP1),
ionizing radiation and reactive oxygen free radicals, can activate inactive latent
the journal of oncopathology 2:4
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The Journal of Oncopathology

Copyright # 2014 Optimal Clinical (Doctors.MD). All rights reserved.
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TGF-b complexes within the extracellular matrix

(ECM).5 It was first discovered in the 1970s and
defined in the early 1980s.69
TGF-b pathway actions depend on cell type,
growth conditions, and the presence of other
growth factors. There are 3 TGF-b ligands (TGFbs 1-3) and 3 high-affinity receptors, namely
TGF-b type I (TbR-I), type II (TbR-II), and type
III (TbR-III or betaglycan). Among the 3 TGF-b
isoforms, TGF-b1 is the most abundant and
most universally expressed. TGF-b elicits its
cellular responses by binding to TGF-b type I
and type II serine/threonine kinase receptors and
phosphorylation of receptor regulated (R-)
SMAD2 and SMAD3. Activated R-SMADs form
heteromeric complexes with common mediator
SMAD4, which accumulates in the nucleus,
where they control gene expression in a cell
type-specific manner. This event is called as
canonical TGF-b signaling. TGF-b receptors
can also activate the bone morphogenic protein
(BMP)regulated SMADs, SMAD1/5/8 which is
called as non-canonical TGF-b signaling. This
causes the acquisition of migratory and invasive
phenotypes in carcinomas and the induction of
proliferative and migratory phenotypes in endothelial cells.4,1012
Mesenchymal-epithelial transition (MET) programs are processes whereby mesenchymal-like
cells transdifferentiate to establish polarized
epithelial-like cells by the completion of the
formation of strong cellcell junctions and
adherens complexes. The decrease of the expression of mesenchymal markers, such as Ncadherin and vimentin, and the increase of the
epithelial markers, such as E-cadherin and CK19, are the characterization of MET programs.
Disseminated tumor cells (DTCs) reinitiate proliferative programs to generate secondary tumors
by MET.1315
This review reveals the evidence demonstrating TGF-b signaling, MET, breast cancer metastasis, and potential therapeutic targets.
TGF-B SIGNALING
Many different cells in the body, including
stromal cells, macrophages, and platelets,
make TGF-b. TGF-b pathways include BMP,
GDF (growth and differentiation factor), activin,
TGF-b, AMH (antimullerian hormone), and
inhibitor pathways. The TGF-b ligands are part
of a large family of proteins including TGF-bs
78
(TGF-b1, 2, 3), inhibins (inhibin bA, bB), the

protein nodal, BMPs (BMP2, 4, 6, 7, 8A, 8B, 9,
10), GDFs (GDF5, 6, 7, 9B, 10, 11, 15[Macrophage Inhibitory Cytokine 1- MIC1], and also
GDF1, 3, 8[Myostatin-MYO],9), AMH, and inhibitors (BMP3, inhibina, inhibinbC and bE,
LEFTYA, LEFTYB). Other components of TGF-b
signaling are receptors (TGFbRI [type-IR],
TGFbRII [type-IIR], TGFbRIII [type-IIIR; betaglycan], R-SMAD); intracellular signal mediators
SMADs (SMAD1, SMAD2, SMAD3, SMAD4
[DPC4 common mediator SMAD {Co-SMAD}],
SMAD5, SMAD8, and I-SMADs [inhibitor
SMADs SMAD6, SMAD7]), p53, FOXO,
CDK2, CDK4; target genes (C-MYC, CDC25A,
cyclin-dependent kinase inhibitors [CDKIs]
[p15INK4B,
P21WAF1/CIP1,
p27KIP1],
COL1A2) and also other converging signaling
pathways (phosphatidylinositol 3-kinase [PI3K]/
AKT, FOXG1, Jagged/Notch, Wnt/Wg, Hedgehog, Her2/Neu, p38 MAP kinase ERK1/2-RAS).
TGFbRI is related with BMP pathway by BMPRIA
(ALK3), BMPRIB(ALK6), ALK1&2; GDF pathway
by BMPRIA(ALK3), BMPRIB(ALK6), ALK2, ActRIB(ALK4), ALK7, TGFbRI(ALK5); activin pathway by ActRIB(ALK4), ALK7; TGF-b pathway by
TGFbRI(ALK5), ALK1&2, BMPRIA(ALK3); AMH
pathway by BMPRIA(ALK3), BMPRIB(ALK6),
ALK2. TGFbRII is related with BMP pathway by
BMPRII, ActRIIA, ActRIIB; GDF pathway by
BMPRII, ActRIIA (activin type II receptor),
ActRIIB; activin pathway by ActRIIA, ActRIIB;
TGF-b pathway by TGFbRII; AMH pathway by
AMHRII. TGFbRIII is related with BMP pathway
by RGMa,b,c(+effect); GDF pathway by Cripto3
(TDGF3)(+effect); activin pathway by Cripto3
(effect), Cripto1 (TDGF1)(+effect); TGF-b
pathway by TGFbRIII(+effect), endoglin(+effect),
Cripto3(effect); inhibitor pathway by TGFbRIII
(effect), Cripto3(effect)11,1618 (Figs. 16).
TGF-b binds to the type-IIR and then phosphorylates the type-IR, and subsequently regulates the SMAD proteins. There is strong
evidence that type-IIR functions as a tumor
suppressor gene. While SMAD1, 2, 3, 5, and 8
play similar roles on positive regulation of the
activity of the type I receptor, SMAD6 and 7 are
thought to regulate negatively. After the formation of hetero-oligomeric complexes with
SMAD4 and translocation to the nucleus, SMADs
function as transcriptional modulators.19
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Ligand
BMP2,4,5,6,7,8A,
8B,9,10
Type RII
Type RI
BMPRII
ActRIIA,
ActRIIB
BMPRIA (ALK3)
BMPRIB (ALK6)
ALK2,ALK1
BMP
Pathway
Type RIII
R-Smad
RGMa, b, c (+)
SMAD1, 5, 8
Co-Smad
I-Smad
SMAD4
SMAD6,7
Figure 1. TGF-b Pathways in Humans: BMP Pathway.
PRECLINICAL EVIDENCE OF TUMOR

SUPPRESSOR AND PRO-ONCOGENIC ROLES
OF TGF-B/TGF-B SIGNALING PATHWAY IN
BREAST CANCER
Preclinical studies in model systems have provided considerable support for a dual role for
TGF-b in breast cancer.2022 TGF-b can act as an
autocrine negative growth regulator in breast
cancer cells.4,23
Intragenic mutation, downregulation, and
loss of TGFbRI and TGFbRII expressions have
been observed in breast carcinomas. Decreased
expression of TGFbRII or mutations in TGFbRI
can occur during carcinogenesis or metastasis of
breast cancer. Expression of wild type TGFbRII
in breast cancer cells that lack a functional
TGFbRII allele demonstrates the tumor suppressor role of TGF-b. Enhanced carcinogen-induced
tumor formation and progression can be seen in
the mammary gland of transgenic mice with the
expression of a dominant-negative TGFbRII.2427

Expression of a dominant-negative TGFbRII in
MDA-MB-231 breast cancer cells also inhibits
bone metastasis by blocking TGF-b-induced
tumor production of parathyroid hormone-related protein (PTH-Rp) that stimulates osteolytic
activity.28 The suppression of TGF-a or chemical
carcinogen-induced tumor formation has been
shown in transgenic over-expression of TGF-b1
in the mammary gland.29 The process of programmed cell death or apoptosis is another
mechanism of TGF-b mediating tumor suppressor activity. The p38 MAP kinase and p160/Rho/
ROCK pathways play a role in TGF-b-mediated
SMAD-dependent growth inhibition of breast
cancer cells. There is a nonredundant manner
of SMAD3 contribution to the induction of
apoptosis in the mammary gland. The inhibition
of CDC25A by the TGF-b-induced p160/Rho/
ROCK activation causes cell cycle arrest.30 It has
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Ligand
GDF5, 6, 7, 9B, 10,
11, 15 (MIC1)
GDF1, 3,
8 (MYO), 9
Type RII
BMPRII
ActRIIA,
ActRIIB
Type RI
BMPRIA (ALK3)
BMPRIB (ALK6), ALK2
ActRIB (ALK4),
ALK7,
TRI (ALK5)
GDF
Pathway
R-Smad
Type RIII
SMAD1, 5, 8
Cripto 3 (+)
SMAD2, 3
Co-Smad
I-Smad
SMAD4
SMAD6,7
Figure 2. TGF-b Pathways in Humans: GDF Pathway.
been shown that TGF-b-receptor activated p38

MAP kinase also mediates SMAD-independent
responses in breast cancer cells.31 Activin can
be produced by breast cancer cell lines in vitro
and it inhibits the proliferation and growth of
ER+ (ER, estrogen receptor) breast cancer cell
lines specifically. Similar to TGF-b, activin binds
to its cell surface receptor and induces the
common intracellular signaling pathway with
SMAD2/3.6,32,33
TGF-b is the potent suppressor of immune
function by inhibiting proliferation, activa
tion, and differentiation of various types of
lymphocytes. TGF-b1 reveals a principal function in the maintenance of immunological
homeostasis.3436
Epigenetic and genetic changes in the breast
cancer cell genome can promote growth, motility, and invasion. In mammary epithelial cells,
80
epithelial-mesenchymal transition (EMT) is stimulated by TGF-b and opposed by BMP.3739

Inappropriate expression of the developmentally
regulated homeoprotein Six1 in MCF7 cells can
induce TGF-b-dependent EMT, promoting
lymph node metastases partly by overexpression
of TGFbRI in mice breast cancer models.40,41
Breast cancer cells do not only produce activin
but also produce inhibin. Inhibin prevents
recruitment of type I receptor and SMAD2/3
activation by forming stable complexes with
ActRII (activin type II receptor) after coupling
with the membrane-bound proteoglycan,
betaglycan (BG), and it induces switching
TGF-b from a tumor suppressor to a tumor
promoter.1,11,42
In breast cancer cell lines, by the blockage of
SMAD3 signaling, oestradiol (E2) can diminish
activin signaling and can also inhibit TGF-b
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Ligand
InhibinA
InhibinB
Nodal
Type RII
Type RI
ActRIIA,
ActRIIB
ActRIB (ALK4)
ALK7
Activin
Pathway
Type RIII
R-Smad
Cripto 3 ()
Cripto 1 (+)
SMAD2, 3
Co-Smad
I-Smad
SMAD4
SMAD7
Figure 3. TGF-b Pathways in Humans: Activin Pathway.
signaling pathway by the degradation of SMAD

proteins with the ubiquitin ligase Smurf. Progesterone (PG) can block TGF-b1 expression and
prevents TGF-b1s tumor-suppressor activity in
MCF7 breast cancer cells.4346
Data from mouse model experiments also
demonstrated that loss of TGFbRII expression
in mammary fibroblasts was linked to tumor
initiation and metastasis.47
Tumor can be described as an unhealed
chronic inflamed wound with various inflammatory cells including Tie2+, VEGFR1+, CD11b+,
and F4/80 + ve myeloid subpopulations, as well
as the innate and adaptive immune cells
natural killer T cells (NKT) and T and B cells.
There are also cancer-associated fibroblasts
(CAFs) and endothelial progenitor cells in tumor
microenvironment. An increased recruitment of
F4/80 + ve macrophages is seen in the fibroblast
stromal composition of the mammary tumor

microenvironment by the loss of TGF-b, so
tumor progresses by the increased expression
of inflammatory genes such as CXCL1 and
CXCL5.4851
In ER breast tumors, as a result of TGF-b
signaling, transcriptional activation of ANGPTL4
(angiopoietin-like 4) which facilitates tumor cell
passage through the lung endothelium causes
site-specific relapse to the lung.52
In a recent in vitro study, two types of the
TGF- pathway antagonists (1D11, a mouse
monoclonal pan-TGF neutralizing antibody,
and LY2109761, a chemical inhibitor of TGF-
type I and II receptor kinases) on sublines of
basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to
lungs (4175TR, 4173) or bones (SCP2TR,
SCP25TR, 2860TR, 3847TR) effectively blocked
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Ligand
TGF 1
TGF 2
TGF 3
Type RI
Type RII
TRI (ALK5)
TRII
ALK1
ALK2
BMPRIA (ALK3)
TGF-
Pathway
Type RIII
R-Smad
TRIII (+)
Endoglin (+)
Cripto 3 ()
SMAD2, 3
SMAD1, 5, 8
Co-Smad
I-Smad
SMAD4
SMAD7
Figure 4. TGF-b Pathways in Humans: TGF-b Pathway.
TGF--induced phosphorylation of receptor- TGF-b signaling by blocking SMAD3 signaling

associated SMADs in all MDA-MB-231 from the type I ALK4 receptor, so pro-oncogenic
subclones.53
activity will be dominant.43,5456 Studies with
archival tissues or circulating TGF-b1 from
breast cancer patients reveal significant correlaCLINICAL EVIDENCE OF TUMOR
tion between intense immunohistochemical
SUPPRESSOR AND PRO-ONCOGENIC ROLES
staining or circulating TGF-b1 and poor survival
OF TGF-b/TGF-b SIGNALING PATHWAY IN
outcome/tumor characteristics.57,58
BREAST CANCER
Higher stromal expression of TFGbRII is
associated
with poor prognosis breast tumors.59,60
Endocrine hormones (gonadotropin-releasing
In clinical perspective, high-grade, large size,
hormone [GnRH], luteinizing hormone [LH],
and
hormone-negative tumors show downregufollicle-stimulating hormone [FSH], oestradiol
lation
of SMADs. Early breast cancer patients
[E2], progesterone [PG] and inhibins [A and B])
have
a
reduced disease free survival (DFS) by the
affect TGF-b signaling pathway. In postmenauposal status, with the loss of inhibin, E2 and PG loss of phosphorylated SMAD2/3.61,62
The advance of gene expression profiling and
decrease the inhibition of the TGF-b superfamily, so activin and TGF-b increase and tumor individual tumor characterizing analysis have
suppressor activity will be dominant. In preme- enabled to identify clinical significance of signalnauposal status, with the cycling inhibin, E2 and ing pathways. Several TGF-b-related gene exPG will increase the inhibition of activin and the pression signatures have been developed. They
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Ligand
AMH (MIS)
Type RI
Type RII
BMPRIA (ALK3)
BMPRIB (ALK6)
ALK2
AMHRII
AMH
Pathway
Type RIII
R-Smad
SMAD1, 5, 8
Co-Smad
I-Smad
SMAD4
SMAD6,7
Figure 5. TGF-b Pathways in Humans: AMH Pathway.
are almost invariably associated with poor prognosis, suggesting the pro-oncogenic activities of
the TGF-b pathway.63,64
Recent clinical studies with an integrated
genomic approach identify the persistent tumor-suppressor effects of TGF-b in human
ER+ breast cancer, but TGF-b deficient signature
is correlated with poor overall outcome and the
TGF-b response signature significantly correlated with ER lung metastasis patient profiles.
Trials with molecular Luminal A subtype patient
population reveal the correlation between the
TGF-b signaling deficiency and poor prognosis.
The increased abundance of TGF-b in the
primary human breast cancer tumor microenvironment correlated with an increased incidence
of distant metastasis.4,51,6567
Metastasis to bone results from the numerous
interactions between cancer cells, haematopoietic stem cells, and normal bone cells within
the bone marrow microenvironment. These
interactions are in turn influenced by multiple

endocrine, paracrine, and physical factors. The
vicious cycle of growth factor and cytokine
signaling between tumor and bone cells progress
homing and cancer spread. Paracrine TGF-b
growth factors influence breast cancer cells in
the bone-pre-metastatic niche. It has been
demonstrated that bisphosphonates have a
direct effect on TGF-b signaling and activin
expression.56,68,69
Using a randomized tamoxifen trial cohort
including in total 564 invasive breast carcinomas, TGFBR2 expression (n 252) and phosphorylation level of downstream target SMAD2
(pSMAD2) (n 319) in CAFs were examined
and links to clinicopathological markers and
prognostic and treatment-predictive values were
assessed. The study revealed that CAF-specific
TGFBR2 expression correlated with improved
recurrence-free survival and multivariate analysis
confirmed CAF-TGFBR2 to be an independent
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Ligand
BMP3, Inhibin,
Inhibin C, Inhibin E,
LEFTYA,
LEFTYB
Type RII
Type RI
Pathway
Inhibitors
Type RIII
R-Smad
TRIII ()
Cripto 3 ()
Co-Smad
I-Smad
Figure 6. TGF-b Pathways in Humans: Pathway Inhibitors.
prognostic marker (multivariate Cox regression,

hazard ratio: 0.534, 95% (CI): 0.3600.793, P
0.002).70
TGF-b-related treatment strategies can be
evaluated at ligand (gene silencing by RNA
interference), ligand-receptor interaction (monoclonal antibodies, natural TGF-b inhibitors,
soluble TGF-b receptors-fusion constructs), and
intracellular signaling levels (small molecule
inhibitors targeting the kinase of TbRs, inhibitors targeting SMADs interaction with TbRsusing peptide aptamers to SMADs). There is a
progress in studies related with targeting TGF-b
signaling pathway.7174
TGF-b antagonists are now in early phase
(phase I/II) clinical trials in oncology in several
tumor types including breast cancer (http://
clinicaltrials.gov Trial NCT01401062), Her2 and
TGFBeta CTLs in Treatment of Her2 Positive
84
Malignancy (HERCREEM) (http://clinicaltrials.

gov Trial NCT00889954), and Phase I Trial of
TGFB2-Antisense-GMCSF Gene Modified Autologous Tumor Cell (TAG) Vaccine for Advanced
Cancer (Auto TAG) (http://clinicaltrials.gov Trial
NCT00684294).
MET/C-MET
Three interrelated themes in current breast cancer
research have been defined: gene addiction,
phenotypic plasticity, and cancer stem cells. A
process opposite to the initial EMT at the primary
tumor site, MET is an evolving and relatively
underinvestigated mechanism contributing substantially to the colonization DTCs into metastatic
tumors at the secondary site7580 (Fig. 7).
For the metastatic colonization of breast
cancer cells, they must undergo MET, so one of
december 2014

Microenviromental factors in metastatic niche
Versican
E-cadherin
repressor genes
MicroRNAs
(Eg.miR-200 family)
ON
(Eg.Snail1/2, Zeb1/2,
Twist1/2, SIP1)
OFF
Cell cycle
genes
(Eg. CyclinD1, D2)
ON
OFF
Tumor Growth
E-cadherin and
other epithelial genes
Eg. Occludin, Claudin,
Cytokeratin, PK3,
Crumbs 3, miR200
ON
Vimentin,
N-cadherin,
Fibronectin
OFF
Epithelial phenotype
(-Catenin expression on cell membrane, WNT signaling )
Figure 7. Schematic Display of MET and Tumor Growth in Metastatic Site.
the mechanisms for MET is the downregulation

of the homeobox transcription factor Paired
related homeobox 1 (PRRX1) which induces stem
cell properties.81
In primary breast cancer, TGF-b first induces
Snail and EMT and then induces ID1 (inhibitors
of DNA binding) in mesenchymal cells. This ID1
binds and inactivates Twist1, causing MET and
promoting the epithelial colonization at the
metastatic site. ID proteins (ID1, ID2, and ID3)
are the key mediators of plasticity at distinct sites
of tumor growth.82,83
On the other hand, MET oncogene (mesenchymal-epithelial transition factor), localized on
chromosome 7 and encoding the dimeric tyrthe journal of oncopathology 2:4
osine kinase receptor for hepatocyte growth

factor (HGF), is involved in cell proliferation,
survival, and angiogenesis.84 TGF-b isoforms
and HGF functions in mammary gland ductal
morphogenesis.85
MET-regulated
invasive
growth has a relevant role in cancer invasion
and metastasis.86 (Fig. 8)
MET gene amplification has been described
in many human cancers including breast cancer.
In the past years, many clinical studies have
revealed MET-receptor overexpression or pathway hyperactivation in tumor tissues of breast
cancer patients and also a strong relationship
between high HGF/MET signaling and tumor
progression/poor prognosis. MET receptor and
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IGF1/IGF1R
(Crosstalk)
SRC/
FAK
STAT3
VEGF/
VEGFR
RAS
HGF/
cMET
ERK/
MAPK
PI3K/
AKT
EGF/EGFR
(Crosstalk)
RON
(Crosstalk)
Figure 8. HGF/cMET Signaling Pathways.
its physiological ligand hepatocyte growth factor

(HGF) or scatter factor (SC) are significantly
overexpressed in triple negative breast carcinomas
(52% of TNBCs) and HGF/c-MET overexpression
is an adverse prognostic factor for triple negative
breast cancer. MET signaling pathway is frequently
altered in basal-like breast carcinomas.8789
Increased MET and HGF gene copy numbers
are associated with trastuzumab failure in HER2positive metastatic breast cancer.90,91
Eribulin mesilate (eribulin), a non-taxane
microtubule dynamics inhibitor, suppresses experimental metastasis of triple negative breast
86
cancer (TNBC) cells by reversing phenotype from

EMT to MET states.92
Preclinical and clinical studies revealed that
MET pathway is a potential therapeutic target.93
MET-targeting agents are also in early phase
(phase I/II) clinical trials in breast cancer. MP470
(SuperGen) (a broad-spectrum kinase inhibitor
targeting MET, Ret, Rad51, mutant forms of Kit,
PDGFR, Fit-3) is tested in neuroendocrine
tumors, lung cancer, and triple negative breast
cancer. Current phase II trials with tivantinib
(small molecule MET inhibitor) and onartuzumab (MetMAb) in recurrent-metastatic TNBC
december 2014

(http://clinicaltrials.gov Trial NCT01575522 and according to the menopausal status and molecular subtypes in breast cancer. MET oncogene
Trial NCT01186991) are ongoing.
and MET signaling pathways are evolving and
relatively underinvestigated mechanisms in
CONCLUSION
breast cancer metastasis and treatment outThere are significant advances in understanding comes. Further research can improve our underthe role of TGF-b/TGF-b signaling pathways standing of the underlying relationship between
in tumor formation, progression, invasion, and these molecular mechanisms and TNBCs/HER-2
metastasis. Because of its paradoxical effects, (+) breast cancers.
tumor-type and metastatic site-specific research
can hopefully lead to discover targets for therapy
AUTHORS DISCLOSURES OF POTENTIAL
and development of biomarkers for appropriate
CONFLICTS OF INTEREST
patient selection and prediction of survival outcome with targeted anticancer therapeutics. The author(s) indicated no potential conflicts of
Trials indicate that the clinical importance of interest.
these pathways must be evaluated differently
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The

Transforming Growth Factor Beta (TGF-b),

ransforming growth factor beta (TGF-b), a potent multifunctional regulatory

the journal of oncopathology 2:4

The Journal of Oncopathology

TGF-b complexes within the extracellular matrix

(TGF-b1, 2, 3), inhibins (inhibin bA, bB), the

the journal of oncopathology 2:4

The Journal of Oncopathology

BREAST CANCER METASTASIS

Figure 1. TGF-b Pathways in Humans: BMP Pathway.

PRECLINICAL EVIDENCE OF TUMOR

expression of a dominant-negative TGFbRII.2427

The Journal of Oncopathology

Figure 2. TGF-b Pathways in Humans: GDF Pathway.

been shown that TGF-b-receptor activated p38

epithelial-mesenchymal transition (EMT) is stimulated by TGF-b and opposed by BMP.3739

the journal of oncopathology 2:4

The Journal of Oncopathology

BREAST CANCER METASTASIS

Figure 3. TGF-b Pathways in Humans: Activin Pathway.

signaling pathway by the degradation of SMAD

stromal composition of the mammary tumor

The Journal of Oncopathology

Figure 4. TGF-b Pathways in Humans: TGF-b Pathway.

TGF--induced phosphorylation of receptor- TGF-b signaling by blocking SMAD3 signaling

the journal of oncopathology 2:4

The Journal of Oncopathology

BREAST CANCER METASTASIS

Figure 5. TGF-b Pathways in Humans: AMH Pathway.

interactions are in turn influenced by multiple

The Journal of Oncopathology

Figure 6. TGF-b Pathways in Humans: Pathway Inhibitors.

prognostic marker (multivariate Cox regression,

Malignancy (HERCREEM) (http://clinicaltrials.

the journal of oncopathology 2:4

The Journal of Oncopathology

BREAST CANCER METASTASIS

Microenviromental factors in metastatic niche

the mechanisms for MET is the downregulation

osine kinase receptor for hepatocyte growth

The Journal of Oncopathology

Figure 8. HGF/cMET Signaling Pathways.

its physiological ligand hepatocyte growth factor

cancer (TNBC) cells by reversing phenotype from

the journal of oncopathology 2:4

The Journal of Oncopathology

BREAST CANCER METASTASIS

factor-b in cancer and metastasis. Cancer

mary Gland Biol Neoplasia. 2011; 16:127

the journal of oncopathology 2:4

persistent tumor suppressive effects of

The Journal of Oncopathology

transforming growth factor-b1 transgene

the progression of oestrogen receptor

the journal of oncopathology 2:4

signalling factors in invasive breast cancers: relationships with age at diagnosis

The Journal of Oncopathology

BREAST CANCER METASTASIS

73. Akhurst RJ, Hata A. Targeting the

80. Gunasinghe NP, Wells A, Thompson

the journal of oncopathology 2:4