Biomedicine & Pharmacotherapy 123 (2020) 109778

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Krüppel-like factors in breast cancer: Function, regulation and clinical T

relevance
Jianping Zhanga,b,1, Guangliang Lic,1, Lifeng Fengb, Haiqi Lua,b,*, Xian Wanga,b,*
a
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
b
Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
c
Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

A R T I C LE I N FO A B S T R A C T

Keywords: Breast cancer has accounted for the leading cause of cancer-related mortality among women worldwide.
Krüppel-like factors (KLFs) Although the progress in its diagnosis and treatment has come at a remarkable pace during the past several
Breast cancer decades, there are still a wide array of problems regarding its progression, metastasis and treatment resistance
Function that have not yet been fully clarified. Recently, an increasing number of studies have revealed that some
Regulation
members of Krüppel-like factors(KLFs) are significantly associated with cell proliferation, apoptosis, metastasis,
Clinical relevance
cancer stem cell regulation and prognostic and predictive value for patients in breast cancer, indicating their
promising prognostic and predictive potential for breast cancer survival and outcome. In this review, we will
summarize our current knowledge of the functions, regulations and clinical relevance of KLFs in breast cancer.

1. Introduction closely implicated with cancer-related regulatory processes and sig-

As for the most common type of cancer and the most frequent cause
of cancer-related mortality among women, breast cancer is the main
reason for leading to over 500,000 deaths per year worldwide [1–3].
Breast cancer is a kind of complicated and heterogeneous diseases,
mainly divided into hormone-receptor positive [4], human epidermal
growth factor receptor-2 overexpressing (Her2+) [5] and triple nega-
tive breast cancer(TNBC) [6] according to different molecular sub-
typing and histological features [7]. Over the last several decades,
breakthroughs have been made in the field of breast cancer treatment
including surgery [8], radiotherapy [9], chemotherapy [6], endocrine
therapy [4], targeted therapy [10], immunotherapy [11] and so on.
However, the pathogenesis of breast cancer initiation and progression
and its drug resistance mechanisms in different subtypes still have not
yet been fully elucidated. Remarkably, a large amount of transcriptional
factors including KLFs have been demonstrated to be associated with
the process of cancer initiation, promotion and progression [12,13].
Named for a mammalian homologue of the Drosophila melanogaster
gene Krüppel identified in 1993 firstly, KLFs are a family of DNA-
binding transcriptional regulators which play essential roles in several
crucial cellular processes such as proliferation, differentiation, apop-
tosis, migration and cancer cell stem regulation [8,9]. To date,
mounting reports have demonstrated that several KLF factors are
naling transduction pathways involved in cell proliferation differ-
entiation, metabolism, apoptosis, invasion and migration, as well as the
establishment and maintenance of cell pluripotency and the initiation,
promotion and progression in breast cancer [14]. Intriguingly, it is
worthy of in-depth exploration that KLFs can function as oncogenes
and/or tumor suppressors in distinct cancer-specific contexts,implying
their potential roles in predicting prognosis in different cancer patients.
Up to now, the function of KLFs have been systematic summarized in
many other diseases such as female reproductive system pathologies
and leukocyte diseases [15,16]. However, there is no comprehensive
generalization of the functions of Krüppel-like factors in breast cancer.
As a result, in this review, we will focus on the latest advances on the
regulation and function of KLFs and highlight their molecular me-
chanisms, biological roles and clinical relevance in breast cancer to
provide a novel therapeutic strategies to breast cancer prevention and
treatment (Fig. 1).
2. Overview of Krupple-like factors
KLFs, get its name from the first discovery of Krüppel protein in
Drosophila melanogaster, a member of the “gap” class of segmentation
gene products that regulates body segmentation in the thorax and
anterior abdomen of the Drosophila embryo [17]. Up to now, 17

⁎
Corresponding authors at: Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
E-mail addresses: haiqilu@zju.edu.cn (H. Lu), wangx118@zju.edu.cn (X. Wang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2019.109778
Received 21 September 2019; Received in revised form 27 November 2019; Accepted 29 November 2019
0753-3322/ © 2019 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
J. Zhang, et al.
Fig. 2. Phylogenetic tree of human KLFs.
According to the structural similarity approximation of DNA-binding domain,
the KLFs family can be divided into three major parts. Subgroup I consists of
KLF3,5,6,7,8,12 which are highly related with each other, Subgroup II consists
of KLF 1,2,4,15,17, the remaining KLFs are belong to Subgroup III. The tree was
generated using Genetic Computer Group (GCG) sequence analysis software
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Biomedicine & Pharmacotherapy 123 (2020) 109778
Fig. 1. The structure of KLF.
KLF family is composed of the conversed C-
terminal regions and highly divergent N-term-
inal regions. C-terminus consists of three
tandem Cys2His2 zinc-finger motifs which act
as a DNA-binding domain recognizing GC rich
target sequences.N-terminus contains tran-
scriptional regulatory domains which can bind
co-factors and contribute to distinct functions
of KLFs.
members of KLFs have been identified in human tissue and got depth
lucubrated. It is well acknowledged that all KLFs members contain
three C2H2-type zinc fingers which is similar to the DNA binding do-
main structure of transcription factor Sp1, therefore, KLFs is a subgroup
of Sp1/KLF family [13]. In conservation and phylogenetic analysis,
KLFs proteins are conserved among mammals from human to rat [15].
However, the tissue expression of the KLFs are varies, most KLFs are
ubiquitously expressed(e.g. KLFs 6, 10, and 11), while others are found
to be developmentally or temporally expressed in tissue- and cell-type
specific manner (KLF1 is expressed predominantly in bone marrow,
KLF2 is highly expressed in adipose tissue, and KLFs 4, 5 are very
abundant in the gastrointestinal tract) [17]. Based on the similarity in
sequences of their DNA binding domains, KLFs can be phylogenetically
analyzed as Fig. 2 which defines evolutionary distances of individual
family members. In the structure, besides above-mentioned DNA
binding domains, transcriptional regulation domain and nuclear loca-
lization signal (NLS) domain are the remaining two parts, although NLS
is only located in several KLFs (KLF 1, 4, 8, 11), which occur im-
mediately adjacent to or within the Zinc-finger motifs, with the function
of nuclear localization of KLF [18]. Specifically, DNA binding domain is
composed of three tandem Cys2His2 zinc-finger motifs in C-terminal
region with the function of recognizing similar target sequences (GC-
rich sequences with a preference for the 5′-CACCC-3′core motif). Due to
this special structure, evolutionally similar KLFs may have same tar-
geting promoters and antagonize their mutual transcriptional activity
mostly because of physical competition. By contrast, the transcriptional
Fig. 3. The role of KLFs in breast cancer
metastasis.
KLFs take part in the process of metastasis in-
cluding EMT, ECM change, invasion and an-
giopoiesis. The specific molecular mechanisms
are shown in Fig. 3. Blue square represents the
upstream of KLFs while the green rhombus
represents downstream of KLFs.Blue-white box
and Red-white box represent negatively and
positively regulate the process of metastases,
respectively. KLF4 negatively regulates angio-
poiesis via inhibiting VEGF expression, KLF8
promotes but KLF6 and KLF9 inhibit EMC
change, KLF8 stimulates invasion by FAK and
EPSTI1 activation, KLF10 downregulates inva-
sion by inhibiting EGFR signal pathway. KLF5
accumulates EMT by promoting Slug tran-
scription,However, BAP1 can deubiquitinate
KLF5 and promote EMT. KLF4 promotes E-
cadherin to restrain EMT development,while
KLF8 inhibits E-cadherin to facilitate EMT.
KLF6-SV boosts EMT by increaing TWIST1 but
KLF17 suppresses EMT through ID-1 inactiva-
tion and this supression can be rescured by DJ-
1 and P53.
J. Zhang, et al.
regulation domain located in N-terminal is highly variable and contain
domains including acidic transactivation domains, Sin-3 interacting
repressor domains and C-Terminal Binding Protein (CtBP)-Binding re-
pressor domains that interact with specific co-activators and co-re-
pressors, resulting in functional diversity and specificity. Interestingly,
It has been reported that there is overlap between Sin-3 interacting
domain and CtBP-Binding domain, indicating that the function of Sin-
3and CtBP may exist completion relationship. By regulating gene
transcription, the function of KLFs are involved in many physiologic
and pathologic processes, such as cell differentiation, proliferation, cell
growth, and apoptosis, during normal development or under different
disease conditions [13].
3. The function of KLFs in breast cancer
3.1. KLFs in cell proliferation
Cell proliferation is one of the important physiological functions of
living cells and an important life feature of organisms which is the basis
for growth, development, reproduction, and inheritance of organisms
[19–21]. Infinite ability to proliferate is a critical hallmark of tumor
cells [22]. During the proliferation, genetic alterations found in cancers
can alter specific regulatory pathways and provide a selective growth
advantage by activation of transforming oncogenes or repression of
tumor suppressors [23]. However, whether the role of KLFs acting as
oncogenes or tumor suppressors has not reach a consensus and need
deeper exploration in the proliferation of breast cancer. Remarkably,
KLF4 is demonstrated as a well-recognized tumor suppressor in breast
cancer by its well-.documented cell cycle inhibition. Mechanically,
KLF4 acts as a transcriptional factor which binds to the promoter of
CDKN1A (p21) and CDKN1B (p27) to promote their transcription and
cell cycle G1/S arrest [24,25]. However, other recent findings reported
that KLF4 may act as oncogene in breast cancer [23,26]. K. Wade Foster
etc revealed that KLF4 is high expressed in breast cancer tissues and
Loss-of-function mutations frequently affect p53 and p16/CDKN2 to
inhibit the proliferation [23]. Another research indicated that trans-
fection of the KLF4 gene inhibited the proliferation of breast cancer
cells MDA-MB-231, suggesting that KLF4 is important for the initiation
and progression of breast cancer [26]. Although these evidences are
limited and controversial, it may provide us a novel perspective on the
role of KLF4 dependent on different cell and tissue situation. Intrigu-
ingly, KLF4α, the splice of KLF4, stimulates breast cancer cell cycle and
proliferation by acting as a KLF4 antagonist through abrogating its
nuclear localization to activate the transcription of target genes such as
CDKN1A and CDKN1B [27]. Similarly, CDKN1A transcription can be
activated by KLF6 while be attenuated by miR-4262 [4,24]. Different
from KLF4, KLF5 is highly overexpressed and functions as an oncogene
in breast cancer cells [28–30]. Mechanically, KLF5 can participate in a
diverse set of biological processes such as chromatin licensing and
modulated a vast array of cell cycle related genes such as cyclin A2
(CCNA2) [31], cyclinD1(CCND1) [32], DNA replication factor 1 (CDT1)
and E2F transcription factor 3(E2F3) [31], which controls cell cycle-
dependent gene expression like fibroblast growth factor binding pro-
tein1(FGF-BP1) [30]. Besides, KLF5 binds to the promoter of micro-
somal prostaglandin E2 synthase1(mPGES1)to facilitate its transcrip-
tion so as to enhance the activity to suppress CDK inhibitors including
p21 and p27 [33]. Furthermore, another research indicated that KLF5
recruits p300 to the promoter of lncRNA RP1 to accelerate its expres-
sion at transcriptional level. The high expressional lncRNA RP1 binds to
translational initiation complex p-4E-BP1/eIF4E to downregulate the
expression of tumor suppressor p27 [34]. Nevertheless, how other KLFs
members regulate cell cycle have not yet been reported. Therefore,
further investigations will be urgent to shed light upon the other KLFs
and how they orchestrate their crosstalk relationship on regulating cell
cycle genes.
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Biomedicine & Pharmacotherapy 123 (2020) 109778
3.2. KLFs in apoptosis
As proliferative and apoptotic signaling pathways are often inter-
connected, many of the factors (p53, E2F, MYC, MAPKs etc) and
pathways important for KLFs in cancer cell proliferation are also re-
levant for apoptosis. Importantly, KLFs can regulate several classical
apoptotic factors such as BAX and survival factors including MCL1,
BCL-2, JNK and so on [14]. It has been reported that KLF5 inhibits
apoptosis through downregulating tumor necrosis factor TNF-α [35]
with increasing the anti-apoptotic factors like B-cell lymphoma-XL(BCL-
XL) [36]. Furthermore, KLF10 promotes breast cancer cell apoptosis via
downregulating the inhibition of BAX (BI-1) expression as well as in-
creasing Ca2+ release from endoplasmic reticulum to cytoplasm in
estrogen-responding adenocarcinoma cells [37,38]. KLF11 enhances
the apoptosis of breast cancer cells by inhibiting the expression of Bcl-2
while upregulating Bax protein level. During the process of apoptosis in
breast cancer cells, KLFs are also modulated by some kinds of ncRNAs
such as microRNAs. The low expression of KLF11 could be caused by
miR-30d through targeting 3’UTR [39]. Moreover, miR-205 can directly
target 3’-UTR of KLF12 and induce the apoptosis. However, the anti-
apoptotic mechanism of KLF12 remained largely unknown [40,41].
Collectively, KLF5 inhibit whereas KLF10, KLF11 and KLF12 accelerate
the apoptosis of breast cancer cells.
3.3. KLFs in tumor metastasis
Metastasis is the spread of cancer to another part of the body distant
from the original primary cancer which occurs through the transfer of
malignant or cancerous cells via lymphatic or blood circulation. During
the process of metastasis, Epithelial–mesenchymal transition (EMT),
extracellular matrix change, invasion and angiogenesis all play critical
roles and have long been the research focus [42–44]. Remarkably, an
increasing amount of reports indicates that KLFs may take part in this
process.
3.3.1. Epithelial-mesenchymal transition
As one of the most well-known characters of malignant transfor-
mation, the epithelial–mesenchymal transition (EMT) is a process by
which epithelial cells lose their cell polarity and cell-cell adhesion, si-
multaneously gain migratory and invasive properties to become me-
senchymal cells [45,46]. The most remarkable character is loss of E-
cadherin which maintains cell–cell contacts and adherent junctions
[47]. E-cadherin is downregulated by transcription factors like Snail,
Slug, RhoB, TWIST1 and some growth factors like TGF-β, EGF, FGF and
IGF-1 [47–50]. Recently, a large amount of researches indicated that
KLFs are highly associated to EMT in breast cancer [28,51]. For ex-
ample, KLF4 inhibits EMT by promoting E-cadherin expression in
transcriptional activation, which is necessary for maintenance the epi-
thelial phenotype [52]. Strinkingly, KLF5 induces EMT by increasing
the expression of slug [29]. Moreover, KLF6-SV, the splice of KLF6,
increases EMT by promoting TWIST1 transcription. Thus KLF6-SV ac-
celerates breast cancer metastasis in mouse models and indicate a poor
survival of breast cancer patients [53–55]. Contrary to KLF4, KLF8
promotes EMT via directly binding to the GT box in the E-cadherin
promoter but represses E-cadherin gene expression [56,57]. Taken to-
gether, these seemingly controversial but plausible explanations about
the consequences of how KLFs regulate E-cadherin might indicate that
further studies should be undertaken to understand subtle differences of
their binding in the promoter of E-cadherin the exquisite and specific
regulation of their downstream target genes and their completely re-
levant biological mechanisms. Compared with the promotive effect of
above-mentioned KLFs in EMT, KLF17 is a negative regulator of EMT by
suppressing the transcription of the inhibitor of DNA binding-1 (ID-1)
which is an important member controlling cancer metastasis [58,59].
Besides, the expression of KLF17 is also regulated by p53 and DJ-1 [59].
Mutant-p53 interacts with KLF17 and antagonizes KLF17 mediated
J. Zhang, et al.
EMT gene transcription such as CD44, PAI-1 and Cyclin-D1 [60]. DJ-1
binds to the promoter of KLF17 to inhibit its transcription [59]. Col-
lectively, an increasing number of KLFs have been recognized to play
pivotal roles in the process of EMT, raising some pending problems that
whether different KLFs are fine tuned to carry out their functions de-
pendent on cancer cell-specific microenvironment. Thus, future in-
vestigations will be urgent to explore their crosstalk and mutual reg-
ulation with each other.
3.3.2. Extracellular matrix (ECM) change
Extracellular matrix (ECM) change is a crucial part of metastasis.
Matrix metallo proteinases (MMPs) can degrade various protein com-
ponents in ECM and destroy the histological barrier of tumor cell in-
vasion, thus playing a key role in tumor invasion and metastasis
[61,62]. For instance, KLF6 can inhibit breast cancer metastasis by
reinforcing Tissue factor pathway inhibitor-2 (TFPI-2) transcription,
which is a matrix-associated Kunitz inhibitor to restrain the activation
of zymogen matrix metalloproteinases [63]. Different from KLF6, KLF8
is a positive regulator of MMPs, which could enhance the activity of
MMP2 but not influence its expression. Besides, as an active upstream
regulator of MMP2, MMP14 is a direct target of KLF8. As a result, KLF8
enhances the transcription of MMP14, which increases the activity of
MMP2. In another part, KLF8 accelerates to form β-catenin/TCF1
transactivation complex which facilitates the transcription of MMP14
[64]. The aforementioned evidences directly demonstrated that KLF8
can promote ECM change in breast cancer [65,66]. Besides, KLF9 boosts
metastasis by impairing matrix metalloproteinase 9 (MMP9) in breast
cancer tissues [67–69]. KLF9 recedes MMP9 by antagonizing NF-κB
p50/p65 binding to the promoter of MMP9. In addition to MMP9, KLF9
also down-regulated several other NF-κB targets such as TNF-α, VEGFA
and uPA in breast cancer cells [68].
3.3.3. Invasion
KLFs are also implicated in the invasion of breast cancer cells. KLF4
positively regulates invasion via activating Notch signal pathway and
promotes migration of breast cancer [70]. Intriguingly, on the one
hand, KLF8 promotes lung metastasis of breast cancer in nude mice by
augmenting epithelial stromal interaction 1(EPSTI1) expression [71]
which interacting Valois-containing protein(VCP)to activate NF-κB
signaling pathway. On the other hand, KLF8 facilitates the transcription
of CXCR4, which towards to CXCL12 and activates focal adhesion ki-
nase (FAK), fascinatingly, as a positive feedback, FAK further enhances
the expression of KLF8 [56]. Nevertheless, KLF10 inhibits breast cancer
cell invasion by descending the transcription of EGFR via binding with
HDAC1 to form a complex, which binds to Sp1 sites on the EGFR pro-
moter and inhibits its transcription by suppressing histone acetylation
[66,72]. Moreover, KLF11 is supposed to be a suppressor in breast
cancer invasion whereas the specific mechanism is still obsure [39].
During the invasion, angiogenesis is recognized as an essential part of
metastasis which delivers nutrition to cancer cells and transfers tumor
cells to a distant site [73]. Vascular endothelial growth factor (VEGF) is
an important angiogenic factor that promotes angiogenesis in a series of
pathological conditions, including cancer, inflammation and ischemic
disorders. Breast cancer cells such as MDA-MB-231 are more aggressive
than normal breast epithelial cell MCF-10A, this transfer ability might
result from the high expression of VEGF. For instance, KLF4 inhibits
angiopoiesis via inhibiting VEGF transcription. KLF4 recruits histone
deacetylases (HDACs) -2 and -3 at the VEGF promoter which is over-
lapping with SAF-1- binding elements, whereas SAF-1 enhances but
KLF-4 attenuates VEGF expression in normal MCF-10A cells, which can
explain the reason why MDA-MB-231cells are more aggressive than
MCF-10A cells [74].
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Biomedicine & Pharmacotherapy 123 (2020) 109778
3.4. KLFs in signaling transduction
3.4.1. Hormone receptors signaling pathway
Hormone receptor signaling pathways play a fundamental role in
the development of breast cancer. The roles of KLFs in estrogen re-
ceptors-related signaling pathways are complicated. For example, oes-
trogen upregulates the expression of KLF4 in protein level. Von Hippel-
Lindau (pVHL), downregulated by estrogen, facilitates accumulation of
KLF4 in a proteolytic regulation way. While KLF4 knockdown inhibits
oestrogen-induced growth of tumor cells [25], which indicates KLF4
acting a positive regulatory role in the proliferation induced by es-
trogen. However, another research indicated that KLF4 suppresses es-
trogen-dependent breast cancer growth by interacting with the DNA-
binding region of ERa, competitively antagonist binding of ERa to es-
trogen response elements at the presence of estrogen, resulting in a
reduction in ERa target gene transcription. In another word, KLF4 in-
hibit only the transcriptional activity not expression of ERα [75]. In a
word, these seemingly controversial but plausible explanations about
the consequences of function of KLF4 in estrogen signal pathway might
indicate that further studies should be undertaken to understand subtle
differences of their functions From my perspective, negative feedback
may be responsible for this controversy, estrogen induce KLF4 accu-
mulation while excessive KLF4 inhibit ERa to estrogen response ele-
ments of target genes at the presence of estrogen. As for whether KLF4
turnover function is dependent on stage-specific microenvironment.
Additionally, KLF5 inhibits the proliferation of ER(+) cells by inter-
acting with ERα to form a complex with the result of target genes in-
activation [76,77]. However, KLF6 inhibits estrogen receptor-mediated
cell growth in ER (+) breast cancer via disrupting the interaction of
ERα and c-Src, ultimately leading to the inactivation of c-Src to MAPK
signaling pathway [78,79]. Moreover, KLF17 attenuates ERα-mediated
signaling by impeding ERα function. As a feedback, ER signaling
pathway inhibits the transcription of KLF17 [80]. Besides, the down-
regulation of KLF17 expression in breast cancer is probably due to
UHRF1-dependent promoter hypermethylation [81]. Above all, further
investigations will be urgent to shed light upon the roles of KLFs in
estrogen signaling pathway and how they orchestrate their crosstalk
relationship with other KLFs members. Besides, Proliferation induced
by progesterone in breast cancer cells is also associated with KLF5.
KLF5, upregulated by progesterone, facilitates cell proliferation in
progesterone-treated breast cancer cells [31,82]. However, other KLFs
have not been identified in this signal pathway, thus, it’s necessary for
further clarification of other KLFs functions in progesterone-receptor
signal pathway, which will break a new path for exploring the me-
chanisms involved in KLFs regulate proliferation.
3.4.2. KLFs and other signaling pathways
Besides hormone signaling pathway, KLFs also participate in several
other signaling pathways like retinoic acid (RA) signaling pathway,
Wnt/β-catenin signaling pathway, Notch signaling pathway as well as
EGFR signaling pathway.
3.4.2.1. Retinoic acid (RA) signaling pathway. KLF2 is downregulated in
breast cancer and acts as a tumor suppressor which is positively
correlated with breast cancer patient survival [83–85]. It inhibits
breast cancer cell growth by shifting retinoic acid (RA) signaling
pathway from the pro-carcinogenic Fatty acid-binding protein 5
(FABP5)/peroxisome proliferators-activated receptor /δ(PPARβ/δ)
pathway to the growth-suppressing cellular retinoic acid-binding
proteinⅡ(CRABPⅡ) / retinoic acid receptor (RAR) pathway [84]. In
another word, KLF2 facilitates the expression of CRABPⅡwith RAR but
suppresses FABP5 with PPARβ/δ [86–88]. Besides, KLF2 can also be
epigenetic silenced by the Polycomb group protein Enhancer of Zeste
Homolog 2 (EZH2), which may explain the low-expression of KLF2 in
tumor samples from breast cancer patients [85].
J. Zhang, et al.
3.4.2.2. Wnt/β-catenin pathway. KLF5 promotes cancer cell
proliferation via stimulating Wnt/β-catenin pathway in triple
negative breast cancer. Mechanically, KLF5 binds to the promoter of
CTNNB1(β-catenin) and reinforce the CTNNB1 transcription.
Interestingly, this promotive function of KLF5 can be upregulated by
lncRNA PVT1. Mechanistically, lncRNA PVT1 promotes the interaction
between KLF5 and deubiquitinase BAP1, preventing KLF5 from
ubiquitination degradation [89]. As a result, accumulated KLF5
continuously activate Wnt/β-catenin pathway and boost breast cancer
proliferation.
3.4.2.3. EGFR and Notch signaling pathway. KLF8 enhances EGFR
signaling pathway to drive breast cancer proliferation by repressing
miR-141 transcription, which targets the 3′-untranslational region of
EGFR, leading EGFR translation activation [90]. Additionally, KLF8
activates Notch signaling pathway by increasing the transcription of
miR-146a, which targets the 3’-UTR of Notch signaling inhibitor
(NUMB),as a result, the obstacle of Notch signaling pathway is
downregulated [65]. Thus, KLF8 takes part in the activation of EGFR
signaling pathway and Notch signaling pathway. Nevertheless, whether
KLF8 simultaneously activate this two pathways or which pathway is
the dominating target is under consideration.
Collectively, these data imply that KLFs play a vital role in gov-
erning proliferation-related signal pathway. However, how they or-
chestrate their crosstalk relationship with other signal pathway remain
to be further investigated.
3.5. KLFs in cancer stem cell regulation
Cancer stem cells are rare immortal cells within a tumor that can
both self-renew by dividing and give rise to many cell types that con-
stitute the tumor. Such cells have been found in various types of human
tumors [91] and might be attractive targets for cancer treatment [92].
Breast cancer stem cells (BCSCs) are a rare population of cells with
critical roles in the initiation, growth, metastasis, and relapse of breast
cancer. BCSCs can enter the circulation and form a secondary tumor.
KLF4 is a general recognized stem-cell related genes which is high ex-
pression in cancer stem cells and increase the stem cell marker (the
ratio of CD44/CD24) no matter in triple-negative or ERBB2 positive
breast cancer with a promotion in self-renewal and brain metastasis
[70,93–95]. However, most of other members of KLFs family have not
yet been fully elucidated, suggesting that further studies are extremely
urgent to explore other members in cancer stem cell regulation.
4. KLFs in post-translational regulation
Post-translational modulation (PTM), which occurs after the com-
pletion of protein translation, regulates protein structures and functions
by covalent addition of functional groups, peptides or other complex
molecules reversibly or irreversibly, leading to extend and diversify
protein properties and enhance the ability of modulating protein sta-
bility, localization and activity themselves or their interacting proteins
[96].
4.1. Ubiquitination
Ubiquitin (Ub), consisting of 76 amino acid residues, is an evolu-
tionarily conserved protein dedicated to tagging target proteins for
degradation. Ubiquitination is a well-recognized PTM process, which
covalently attaches Ub to the modified proteins and regulates their
stability, functions and localizations involved in multiple cell functions
and diseases, especially in cancer development [97,98]. KLF4 has re-
cently been demonstrated as a novel substrate of ubiquitin ligase SCF-
FBXO32, which physically interacts with the N-terminus (1–60 aa) of
KLF4 via its C-terminus (228–355 aa) and directly targets KLF4 for
ubiquitination and degradation. Besides, p38 mitogen-activated protein
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Biomedicine & Pharmacotherapy 123 (2020) 109778
kinase pathway is implicated in FBXO32-mediated ubiquitination of
KLF4 [99]. KLF5 can be modified by ubiquitin E3 ligases such as
WWOX, FBXW7, WWP1 [100–102], facilitating KLF5 degradation in a
proteasome-mediated degradation. On the contrary, some deubiquiti-
nases like ATXN3L, BAP1, USP3 exert their activitation to deubiquiti-
nate and stabilize KLF5 so as to promote proliferation in breast cancer
cells [103,104]. Mechanismly,take USP3 for example, C terminus of
USP3 interacted with N terminus of KLF5 to downregulate the ubiqui-
tinate level of KLF5 and promote proliferation of breast cancer [105].
4.2. Methylation
Protein methylation generally refers to the methylation of arginine
[106] or lysine in a protein sequence [107]. Arginine can be methylated
once (called monomethylarginine) or twice (arginine methyltransferase
(PRMTs) simultaneously transfer two methyl groups to the same ni-
trogen at the end of the arginine polypeptide a symmetric methylargi-
nine at the atom, or a methyl group at each nitrogen end to become a
symmetric dimethylarginine [106]. Zhou Z etc found that KLF4 could
be methylated by PRMT5, whose methylation on amino acids R374,
R376, and R377 counteracts VHL/VBC-mediated KLF4 ubiquitination,
averting degradation of KLF4 and promotes breast cancer proliferation
[108].
5. KLFs in prognosis, treatment and drug resistance
5.1. Prognosis
As KLFs play key roles in the development of breast cancer, the
expression level of KLFs can be a potent prognostic factor for patients
with breast cancer. KLF4 is associated with lower pCR in locally ad-
vanced breast cancer patients undergoing neoadjuvant chemotherapy,
suggesting that KLF4 may serve as a predictor for pCR in patients with
breast cancer after neoadjuvant chemotherapy [109]. However, in
triple-negative breast cancer patients, KLF4 higher-expression group
had more favorable overall survival (OS) and disease-free survival
(DFS) rates than KLF4 lower-expression group [110]. As a result, KLF4
functions as a biomarker depending on the type of breast cancer and
whether received treatment. Positive expression of KLF5 is significantly
associated with increased risk of recurrence and worse clinical outcome
in breast cancer patients [82]. In addition, KLF5 is positively correlated
with HER2 and Ki67 expression but negatively correlated with the age
of the patients at diagnosis [111]. KLF6-SV is a marker of increased
metastatic potential indicating poor survival which is higher in patients
with metastasis than in patients without lymph node metastasis [53].
Nevertheless, KLF10 is negatively associated with outcomes. Low ex-
pression of KLF10 predicts malignancy, lymph node metastasis and
poor survival [112]. To a certain extent, KLF10 could give a hint about
the status of ER and the response to endocrine therapy [113] (Table 1).
5.2. Treatment and drug resistance
As KLFs control multiple processes and are indispensable for proper
function of the breast cancer. KLFs were proposed to be potential
therapeutic targets. Zoledronic acid, used for the treatment breast
cancer bone metastases, can upregulate the expression of KLF2 and
KLF6 and induce apoptosis in MCF7 cells [83,114]. Besides, KLF5 acts
as an oncogene in the triple-negative breast cancer, and a large amount
of drugs exert their functions by depending on restraining the expres-
sion of KLF5. For example, Mifepristone, a progesterone receptor (PR)
and glucocorticoid receptor (GR) antagonist which is widely approved
for abortion can inhibit triple-negative breast cancer by downregulating
KLF5 translation through mi-R153 binding to the 3’-UTR in transcripts
of KLF5. Mithramycin A, a DNA and RNA polymerase inhibitor, can also
inhibit KLF5 in protein level in triple-negative breast cancer, but the
mechanism is still not certain [115–117]. Velcade, a proteasome
J. Zhang, et al. Biomedicine & Pharmacotherapy 123 (2020) 109778

Table 1
KLFs in the breast cancer.
Name Process Regulation Biological functions Ref

KLF2 Proliferation down Shift RA signaling fromFABP5/PPARβ/δ to CRABP2/RAR [84]

KLF4 Cycle cycle down promote the cell cycle inhibitor p21, p27 [75]
metastasis down Inhibit VEGF transcription [74]
KLF4α Proliferation up recruit KLF4 to form complex and antagonize the role of KLF4 [27]
KLF5 proliferation up upregulate the cell cycle genes cyclin A2, cyclinD1, downregulate CDK inhibitors like p21 and p27 [28,29]
apoptosis down downregulate TNF-a and increase the anti-apoptotic factors like MCL1 and BCL-XL [39]
metastasis down upregulate E-cadherin [13]
KLF6 proliferation down promote CDKN1A transcription [78]
metastasis down upregulate E-cadherin [56]
KLF6-SV metastasis up Promote the transcription of TWIST1 [53]
KLF8 proliferation up Upregulate cyclinD1 [65]
metastasis up repress E-cadherin gene expression, [60,67–70]
promote MMP9 and MMP14 expression
KLF9 metastasis down Inhibit MMP9 expression [71,72]
KLF10 proliferation down The mechanism is not mentioned [26]
apoptosis up modulation of BI-1 (inhibition of BAX) expression and Ca2+ homeostasis [41]
KLF11 apoptosis up inhibit Bcl-2 expression, whilst upregulate Bax protein level [43]
KLF12 apoptosis down The mechanism is not mentioned [44,45]
KLF17 proliferation down attenuates estrogen receptor alpha-mediated signaling [28]
metastasis down Inhibit ID-1 expression [62]

inhibitor, accelerates breast cancer apoptosis by upregulating tumor
suppressor KLF10 via inhibiting it’s proteolytic degradation [38]. Re-
markably, Melatonin, 2-Hydroxycinnamaldehyde and Paclitaxel can
stimulate KLF17, a suppressor of EMT and metastasis in breast cancer,
to play its repressive role in the metastasis of breast cancer [118–120].
What’s more, with the extension of the treatment cycle and disease
progression, drug resistance, a daunting challenge to the successful
treatment for breast cancer is gradually emerging. KLFs are related with
this process involved in endocrine therapy resistance, Anti-Her2 treat-
ment resistance and chemotherapy resistance. For instance, in tamox-
ifen resistance breast cancer patients, KLF4 is downregulated and
overexpression of KLF4 can contribute to TAM sensitivity via inhibiting
phosphorylation modification of ERK and p38 signaling, suggesting that
enhancing KLF4 expression may be a potential therapeutic strategy for
breast cancer treatment, especially for the TAM-resistant patients. Be-
sides, in Her-2 positive breast cancer, inhibiting the expression of KLF4
and KLF5 can rescue Lapatinib resistance by downregulating anti-
apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-
extra-large (BCL-XL) [36]. Lacking of hormone receptor and Human
epidermal growth factor receptor 2, chemotherapy is the mainstay of
treatment for triple-negative breast cancer (TNBC). Dexamethasone
induces the drug resistance of docetaxel and cisplatin partially through
up-regulating KLF5 in protein level in TNBC, thus targeting KLF5 may
provide a promising therapy to overcome chemotherapy resistance
[121] Collectively, we summarize of note small molecular compounds
capable of modifying expression and activities of KLF family in Table2.
6. Conclusions and perspectives
As DNA-binding transcriptional regulators, KLFs control a series of
essential cellular processes such as proliferation, differentiation, apop-
tosis and migration in breast cancer. The levels of KLF factors are al-
tered during the development of breast cancer. Thus, KLFs might be
potential markers to indicate the malignancy of breast cancer.
Importantly, targeting KLFs is proposed as a novel and feasible ap-
proach in breast cancer treatment and prevention. Significant pro-
gresses have been achieved in understanding the mechanisms by which
how KLFs function. However, there are still an amount of questions to
be solved. For example, whether some KLFs have other functions be-
sides transcriptional role is still unclear. Some KLFs play promotive
roles in the development of breast cancer, but whether these factors
have synergistic or contrary effect remains to be further explored. So
far, it is obscure that how the organism balances the relationship be-
tween oncogenetic KLFs and tumor suppressive KLFs, maybe depending
on identical cellular context and tissue-restricted function. During the
process of tumorigenesis when a KLF expression is altered, other KLFs
will make compensatory changes, compensating for its function to keep
the body in a steady state, and when the external stimulus exceeded the
scope of compensation, some other KLFs will have positive feedback,
making the body develop towards cancer. Besides, the organism ba-
lanced the relationship between oncogenes and tumor suppressors is
dependent on the expression levels of different KLFs, like teeter-board,
which leans to the heavier. Moreover, tumor microenvironment, on-
cogenic mutations, genomic instability and distinct cancer-specific
contexts are also orchestrated to break this balance. In addition, the
problem that drugs targeting some oncogenes may attenuate other

Table 2
Agents That Target KLF Proteins in breast cancer.
Compound Affected KLF family Mode of action Ref
members

Zoledronic acid KLF2, KLF6 Zoledronic acid upregulate the tumor suppressors KLF2 and KLF6 and induce apoptosis [83]
Mifepristone KLF5 Mifepristone suppresses the expression of KLF5 through inducing the expression of miR-153 and induce apoptosis [115]
Mithramycin A KLF5 MithramycinA suppress KLF5 transcription and induce apoptosis [116]
Homoharringtonine KLF10 Homoharringtonine upregulate KLF10 and increase BAX2 and Bim, meanwhile decrease Bcl-2 and BCL-XL, active [38]
Velcade caspase3.
Melatonin KLF17 Melatonin reduce DJ-1 and ID-1 expression and increase the transcription of KLF17, what,s more, Melatonin [118]
induce GSK3-beta nuclear localization and suppress Snail and rise E-cadherin expression to inhibit EMT
2-Hydroxycinnamaldehyde KLF17 Same to Melatonin [119]
Paclitaxel KLF17 Paclitaxel reduce DJ-1 and ID-1 expression and increase the transcription of KLF17 [120]

6
J. Zhang, et al.
tumor suppressors due to the homology of KLFs is also worthy of under
consideration. Collectively, better understanding of KLFs in breast
cancer and clarifying their intrinsic molecular mechanisms will provide
ideas for the development of novel cancer therapeutic intervention in
breast cancer.
Declaration of Competing Interest
We had no conflict interest to claim.
Acknowledgements
This work was supported by Zheng Shu Medical Elite Scholarship
Fund. The National Natural Science Foundation of China (81702976).
Zhejiang TCM science and technology program (2014Zb069). Zhejiang
Provincial Program for the Cultivation of High-Level Innovative Health
Talents.
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