Keywords
kisspeptin - KISS1R - triple negative breast cancer - metastasis - tumor invasion
Breast cancer is the most common noncutaneous malignancy among women worldwide. In
2018, over 2 million new cases and 627,000 deaths were reported globally with countries
such as Belgium, France, Australia, and the United Kingdom having the highest rates.[1] In the United States in 2019, over 268,000 new cases have been reported with over
41,000 deaths.[2] Triple-negative breast cancer (TNBC) represents a particularly deadly form of breast
cancer that occurs more commonly in women younger than 50 years, particularly those
of African American and Hispanic descent.[3] TNBC patients have poor prognosis and the tumors are typically high grade and metastatic.
TNBC tumors are defined by a lack of estrogen receptor-α (ERα), progesterone receptor,
and human epidermal growth factor 2 (HER2, also known as ErbB2).[4]
[5] TNBC remains the most difficult breast cancer subtype to treat, as TNBC patients
do not benefit from the hormone receptor or HER2-targetting drugs used for other breast
cancer subtypes. Additionally, these tumors become rapidly resistant to standard chemotherapies.
Thus, an urgent need remains to identify new molecular targets for effective treatment
of TNBC.
The KISS1 gene is a metastasis-suppressor gene discovered in melanoma cells and its name reflects
both its suppressor sequence and its place of discovery in Hershey, PA, the home of
Hershey's Kisses chocolates.[6] The KISS1 gene encodes a 145 amino acid product that is proteolytically cleaved in the blood
by furin and matrix metalloproteinases (MMPs) such as MMP-9 and the membrane type
I matrix metalloprotease (MT1-MMP), into shorter kisspeptin peptides 10, 13, 14, or
54 amino acid in length.[7]
[8] All kisspeptins have an amidated C-terminal end required for binding and activating
the kisspeptin receptor (KISS1R), a G protein-coupled receptor previously known as
GPR54.[8] KISS1R is a Gq/11-coupled receptor, and upon ligand binding triggers phospholipase C activation, Ca2+ mobilization, and phosphorylation of mitogen-activated protein kinase (MAPK, ERK1/2)
and p38.[9]
[10]
[11] All KPs exhibit similar affinity for KISS1R; however, KP-10 is the agonist of choice
for most studies.[12]
[13]
[14] KISS1 and KISS1R are expressed in healthy breast tissue and play an essential role
in mammary gland formation.[9]
[10]
[11]
The KISS1/KISS1R signaling pathway has anti-metastasis/anti-tumorigenic roles in many
cancers such as melanoma, pancreas, bladder, colorectal, ovary, and prostate, as previously
reviewed.[15]
[16]
[17]
[18] Mechanistically, the tumor-suppressive role has been linked to an inhibition of
tumor invasion via a repression of MMP-9 expression and activity, and by inhibiting
MAPK.[19]
[20]
[21]
[22] Proteases such as MMP-9 promote tumor invasion by degrading the extracellular matrix
(ECM). KISS1 expression is lost in certain cancers such as colorectal and bladder cancer, due
to epigenetic modifications of the KISS1 promoter and this has been linked to poor patient survival.[16]
[23]
[24]
In the last decade or so, several studies have shown that in marked contrast to its
anti-tumor roles in most cancer, KISS1R signaling can promote cell migration and invasion
in ERα-negative breast cancer such as TNBC. It is important to note that in the human
carcinoma, MDA-MB-435 cells which were originally classified as a “breast cancer”
line, KISS1 was reported to act as a metastasis suppressor.[25] However, since then MDA-MB-435 cells have been found to express genes resembling
melanoma cells and thus are no longer considered a robust breast cancer cell model.[26]
[27]
[28] Here, we review the underlying mechanisms by which KISS1/KISS1R signaling promotes
metastasis in various breast cancer models such as established human breast cancer
cell lines, animal models, and clinical samples. KISS1 appears to exhibit a dual role
as an anti- and pro-tumor signaling molecule, as observed for c-MYC,[29] AMP-activated protein kinase (AMPK),[30] transforming growth factor-β (TGF-β),[31] and NFkB[32] to name a few, emphasizing the importance of studying cancer in biological context.[33]
Metastasis
Metastasis is the process by which cancer cells detach from the primary tumor, invade
through the surrounding ECM, and migrate via the blood stream or lymphatics and colonize
at secondary sites.[34] For breast tumors, these sites commonly include the brain, lungs, liver, and bone.[35] When tumors are confined to breast tissue, the 5-year survival rates exceed 90%.[36] However, once metastasis occurs, survival decreases rapidly depending on the extent
and sites of tumor colonization.[37] Initial separation and spreading of cancer cells from the primary tumor involves
a process known as epithelial-to-mesenchymal transition (EMT).[38]
[39] Epithelial cells undergoing EMT lose their cell-to-cell adhesion and cell polarity
as well as the expression of epithelial markers such as E-cadherin and gain the expression
of mesenchymal markers such as MMP, N-cadherin, vimentin, and β-catenin ([Fig. 1]). These cells also acquire a spindle-shaped morphology characteristic of fibroblasts
and gain the ability to migrate and invade through the basement membrane into the
surrounding ECM.[38] Cells which undergo EMT migrate away from primary tumors through cycling of adhesion/de-adhesion
molecules regulated by integrins and by forming F-actin stress fibers through which
myosin cycling initiates cell movement.[40]
Fig. 1 Characteristics of epithelial cells undergoing epithelial-to-mesenchymal transition
(EMT). Epithelial-like cells (shown on the left) have cell polarity, are nonmotile
and noninvasive, and have cell–cell adhesion molecules such as E-cadherin. Mesenchymal-like
cells (shown on the right) lack cell–cell adhesions and have a fibroblast-like morphology
with front-rear polarity, increased motility, and invasiveness.
The ability of tumors to metastasize is dependent on the formation of invasive structures
called invadopodia that mediate tumor cell entry into blood vessels (i.e., intravasate)
or surrounding tissues (i.e., extravasate).[41] Invadopodia are actin-rich, foot-like, adhesive membrane protrusions that form on
tumor cell surfaces ([Fig. 2a]). These are used to digest components of the ECM to create paths used for invading
through tissues via the focal delivery of proteases such as MT1-MMP.[42] Key invadopodia proteins such as cofilin and cortactin regulate invadopodia stabilization
and maturation and the actin cytoskeleton for invadopodial function.[43] The capacity of tumors to form invadopodia is closely linked with the tumor's invasive
and metastatic potential.[44]
[45]
[46] Targeting pathways that regulate invadopodia formation are being tested clinically
in many cancers, including TNBC, as a way of blocking metastasis.[47]
Fig. 2 Invadopodia formation by cancer cells. (a) Triple negative breast cancer (TNBC) cells form invadopodia, foot-like structures,
upon stimulation by growth factors or kisspeptin. These are actin-rich membrane protrusions
that stimulate cell invasion through the extracellular matrix (ECM) via accumulation
of proteases such as membrane type I matrix metalloprotease (MT1-MMP). (b) Confocal image shown on the left showing the co-localization (yellow, arrows) of
endogenous kisspeptin 1 receptor (KISS1R, red) and MT1-MMP (green) in TNBC MDA-MB-231
cell invadopodia. (c) KISS1R signaling promotes the activity of MT1-MMP via mitogen-activated protein
kinase (MAPK, ERK1/2) to thereby promote ECM degradation. KISS1R via β-arrestin2 regulates
the activity of invadopodia proteins; cortactin and cofilin regulate cytoskeleton.
TNBC: Current Treatment
The subtyping of breast cancers into molecular phenotype based on the expression of
ER, progesterone receptor, and HER2 has transformed the way in which breast cancer
is treated by permitting the tailoring of treatments specific to each intrinsic subtype.[48] Although the subtypes are defined by microarray-based gene expression, the clinical
surrogate for this is immunohistochemical testing of protein expression. In TNBC,
the lack of ER, progesterone receptor, and HER2 expression limits therapeutic options
to standard cytotoxic anthracycline and taxane-based chemotherapy with higher rates
of treatment resistance and metastases. Thus, TNBC is the most challenging to treat
and with the worst prognostic outcomes.[5]
With the absence of specific biomarkers in TNBC cells, researchers have been looking
to exploit the rich epithelial-like and mesenchymal-like cancer stem cells by targeting
pathways upregulated in these cells[49]; however, these findings are in the early discovery phase. The main categories of
therapies for TNBC currently being introduced into the clinical realm, albeit with
limited data,[50] include (1) poly-ADP-ribosyl polymerase (PARP) inhibitors in the metastatic setting,[51] given in combination therapy with DNA damaging alkylating chemotherapeutics (e.g.,
platinum) to patients with tumors lacking functional BRCA1 or BRCA2 genes (with resultant impaired ability to repair double-stranded DNA damage); (2)
AKT inhibitor (ipatasertib), which has shown modest efficacy in progression-free survival[50]; and (3) immunotherapy agents, for example, checkpoint inhibitors to programmed
cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). PD-1 and PD-L1
bind to sites of DNA damage to target repair pathway activation. Immunotherapy drugs
are given as single-agent therapies or combination therapies, with ongoing trials
evaluating their efficacy in neoadjuvant, adjuvant, and metastatic settings.[52]
[53] However, clinical trial results indicate lower-than-expected impact on survival
with checkpoint inhibitors in the metastatic setting and thus combination therapies
with targets directed at EMT-related pathways are being explored.[54] Additionally, TNBC tumors exhibit extensive epigenetic alterations via DNA methylation
and novel drug targets aimed at epigenetic re-programming such as BET bromo-domain
inhibitors alone or in combination with immunotherapy are targeted for hypermethylated
tumors and are also in clinical trials.[5]
[55]
Molecular pathways that modulate tumorigenesis are deregulated in the aggressive TNBC
phenotype. Although there appears to be some promising new therapies, there is a dire
need for prognostic biomarkers and specific protein targets for drug development in
TNBC. One significant potential target is KISS1R, and remainder of this review will
highlight the role of KISS1R in regulating TNBC metastasis and chemotherapy resistance.
KISS1R: Metastasis Promoter
KISS1R: Metastasis Promoter
The first landmark study that revealed KISS1R promotes breast cancer metastasis came
from Cho et al who used a mouse mammary tumor virus–polyoma virus middle T antigen
(MMTV-PyMT) model of breast cancer metastasis.[56] In this model, the expression of the PyMT oncogene was driven by the MMTV promoter
and transformation of the mammary epithelium led to the development of metastatic
lesions in the lungs and lymph nodes, in addition to mammary adenocarcinomas.[57]
[58] The study showed that Kiss1r haploinsufficiency (Kiss1r +/−) led to delayed breast tumor initiation, growth, and metastasis. To show a direct
effect on tumorigenesis, the authors conducted orthotopic injections of isolated mouse
primary breast cancer MMTV-PyMT/Kiss1r
+/− cells into the mammary fat pads of mice and observed a reduction in primary tumor
growth compared with mice injected with MMTV-PyMT/Kiss1r
+/+ cells. Thus, loss of Kiss1r expression reduced tumor growth. Importantly, the authors verified that there were
no pubertal defects of mammary gland development in the Kiss1r heterozygotes that would have resulted in impaired mammary tumor development. The
authors also isolated breast tumor cells from primary tumors of PyMT/Kiss1r
+/+ and PyMT/Kiss1r
+/− mice and found that Kiss1r heterozygosity negatively regulated tumor cell proliferation, cell motility, and
invasion. Mechanistically, the study found that Kiss1r heterozygous (PyMT/Kiss1r+/−
) tumors displayed a significant reduction in MMP-9 mRNA compared with wild-type (PyMT/Kiss1r+/+
) tumors. Additionally, KISS1R signaling was found to activate the small G protein,
RhoA, a key regulator of the cytoskeleton necessary for cell migration and invasion
downstream of Gαq activation, through Gαq-p63RhoGEF-RhoA signaling pathway ([Fig. 3]).
Fig. 3 Kisspeptin/KISS1R signaling pathways in triple negative breast cancer (TNBC). In
breast epithelia lacking estrogen receptor (ERα) which negatively regulates KISS1/KISS1R
expression, KISS1R promotes malignant transformation by inducing epithelial-to-mesenchymal
transition (EMT), resulting in a decrease in E-cadherin expression and acquisition
of mesenchymal markers and promoting stress fiber formation. Activation of KISS1R
stimulates TNBC invasion by stimulating invadopodia formation and by activating the
epidermal growth factor (EGFR) via β-arrestin2 and ERK/MMP-9-dependent pathways. KISS1R
can also stimulate invasion via fibulin-3, which regulates MMP-9 activity. Lastly,
KISS1R can signal via RhoA to regulate the cytoskeleton. Blue solid lines represent
KISS1R interacting proteins; black dashed lines represent EGFR interacting proteins.
DAG, diacylglycerol; ERK, extracellular signal–regulated kinase; IP3, inositol-(1,4,5)-trisphosphate; KP, kisspeptin; MMP-9, matrix metalloproteinase-9;
PLC, phospholipase C; PKC, protein kinase C.
KISS1/KISS1R: Regulation by ERα
KISS1/KISS1R: Regulation by ERα
Estrogen signaling via ERα critically regulates the development of the mammary ducts
during puberty.[59] ERα signaling is an important regulator of breast carcinogenesis,[60] and silencing ERα has been shown to induce EMT.[61] It is well known that estradiol (E2) directly regulates KISS1 expression in the hypothalamus. Specifically, in the arcuate neurons, ERα negatively
regulates KISS1.[62] Similarly, ERα has been shown to regulate KISS1 and KISS1R in breast carcinoma.
Marot and colleagues showed that treatment of ERα-positive luminal breast cancer cells
T47D and MCF7 with Tamoxifen, an ERα antagonist, stimulated the expression of KISS1/KISS1R mRNA.[63] Furthermore, women with ERα-positive breast tumors treated with Tamoxifen had high
KISS1 and KISS1R mRNA levels, which is associated with poor prognosis.[63] Clinically, KISS1 and KISS1R levels are higher in ERα breast tumors compared with ERα+ tumors and this correlates
with poor patient outcome.[37]
[64] Thus, ERα signaling downregulates the expression of KISS1/KISS1R and when ERα is lacking, this results in an upregulation of KISS1/KISS1R in breast carcinoma. This was also observed to occur in TNBC cells. When ERα was
overexpressed in TNBC MDA-MB-231 breast cancer cells, treatment of cells with E2 resulted
in a decrease in KISS1/KISS1R mRNA and protein levels, compared with controls.[19]
[63] In support of this, KISS1/KISS1R mRNA and protein levels were found to be upregulated in primary tumor biopsies compared
with healthy breast tissue and KISS1 and KISS1R protein was found to be immunolocalized
in invasive ductal carcinoma in TNBC tumors.[65] Taken together, the presence of ERα in breast epithelia appears to critically regulate
the expression of KISS1/KISS1R.
KISS1/KISS1R: Malignant Transformation
KISS1/KISS1R: Malignant Transformation
The normal (nonmalignant) human MCF10A breast epithelial cells are a widely used model
to study breast cell function as well as cell transformation.[66]
[67] These cells express mammary gland-specific markers resembling normal human breast
and form mammary acini that are capable of secreting milk.[68] Although MCF10A cells express KISS1R endogenously,[19] they lack ERα.[66] This cell model is used commonly to study EMT-like processes in human breast.[69]
[70]
[71] KP-10 treatment or stable overexpression of KISS1R in MCF10A cells promoted an EMT-like
event, resulting in the loss of E-cadherin from cell–cell junctions, the acquisition
of mesenchymal markers such as N-cadherin and Snail/Slug and cells become migratory
and invasive.[19] This divulged that KISS1R signaling in breast epithelia lacking ERα can promote
malignant transformation ([Fig. 3]).
Metastatic breast cancer cells such as TNBC cells, MDA-MB-231, and Hs578T exhibit
high expression of KISS1 and KISS1R in contrast to weakly invasive, ERα-positive breast
cancer cells (T47D, MCF7) or nonmalignant breast MCF10A cells.[65] Depletion of KISS1R in TNBC cells using RNA interference reduced the expression
of mesenchymal markers and stress-fiber formation and impaired invadopodia formation
concurrent with their ability to migrate or invade.[72]
Normal cells, in contrast to transformed cells, depend on cell to ECM contact to be
able to grow and divide. In the absence of a substrate to attach to, normal cells
undergo apoptosis.[73] In contrast, transformed cells such as tumors have the capability to grow and divide
without the need of a substrate and this is a hallmark of carcinogenesis.[74] Thus, tumor cells can form colonies in an anchorage-independent manner and this
ability can be evaluated using an anchorage-independent growth assay, also known as
soft agar colony formation assay. Loss of KISS1R expression in TNBC cells reduced
the ability of TNBC cells to form colonies on soft agar, further implicating a role
for KISS1R in malignant transformation of breast epithelia.[72]
KISS1/KISS1R: Tumor Cell Invasion
KISS1/KISS1R: Tumor Cell Invasion
Using several TNBC cell lines (MDA-MB-231, Hs578t, SCP2, and SUM159) and ERα-negative
cells (MCF10A, SKBR3),[19]
[65]
[72]
[75]
[76]
[77] KISS1R signaling has been shown to promote cell migration and invasion, vital processes
for metastasis. These have been observed in response to stimulating cells with KP-10.
Using a gain-of-function model, the overexpression of human KISS1R in ERα-negative cells, normal MCF10A cells,
and SKBR3 breast cancer cells (which have low levels of endogenous KISS1R) also induced
cell migration and invasion.[19]
[65] Furthermore, KISS1R overexpression in SKBR3 cells triggered tumor cells extravasation
using the chick chorioallantoic membrane assay. KP-10 treatment of cells further increased
the number of tumor cells that extravasated into the stroma, whereas a KISS1R antagonist
(P-234) blocked the KP-10-mediated effect. This provided the first evidence that human
KISS1R signaling regulates breast cancer invasion in an in vivo context.
In human TNBC cells, KISS1R signaling promotes cell invasion by several mechanisms
([Figs. 2] and [3]). First, KISS1R stimulates invadopodia formation by activating key invadopodia proteins,
cortactin, cofilin, and MT1-MMP, through a β-arrestin2 and ERK1/2-dependent mechanisms.[78] Second, KISS1R activates the tyrosine kinase receptor epidermal growth factor receptor
(EGFR or ErbB1) and stimulates TNBC invasion via β-arrestin2 and MMP-9.[19]
[79] In fact, KISS1R directly binds EGFR in TNBC cells and KP-10 enhances this interaction.[79] Treatment of TNBC cells with the KISS1R antagonist, P-234, inhibited KP-10-induced
invadopodia formation, cell invasion, and EGFR activation, implicating a role for
KISS1R signaling in these processes.[19] EGFR signaling promotes cell growth and survival[80] and TNBC frequently (50–70%) overexpresses EGFR.[81] This overexpression correlates with a loss of estrogen responsiveness and a poor
patient prognosis.[82] EGFR expression itself is negatively regulated by ERα.[83] Unfortunately, anti-EGFR therapies alone have not been effective in treating TNBC.[84]
KISS1R is localized to the leading edge in lamellipodia of migratory breast cancer
cells, co-localizing the actin-scaffolding protein, IQGAP1.[19] KISS1R binding to IQGAP1 is necessary for EGFR activation that promotes TNBC invasion.
However, KP-10 failed to activate EGFR or stimulate cell invasion of ERα-positive
MCF7 and T47D cells, or upon expression of ERα in TNBC cells.[19] This implies that ERα signaling keeps KISS1/KISS1R function in check, in addition
to negatively regulating their expression.
Another way by which KISS1R signaling stimulates cell invasion is via the secreted
ECM protein, fibulin-3, also known as epidermal growth factor (EGF)-containing fibulin-like
extracellular matrix protein 1 (EFEMP1). Fibulin-3 is a secreted glycoprotein found
in the ECM, known to regulate cell–matrix interactions, tissue remodeling, cell morphology,
cell adhesion, and motility.[85] A recent study found using transcriptome analysis that fibulin-3 was expressed in
cancer exosomes, which are extracellular vesicles released by cancer cells known to
regulate organ-specific metastasis.[86] The fibulin-3 gene, EFEMP1, was found to be amplified in TNBC in contrast to other breast subtypes and plasma
fibulin-3 levels were found to be elevated in TNBC patients compared with healthy
subjects.[75] Furthermore, KISS1R signaling was found to induce fibulin-3 mRNA and protein expression
as well as fibulin-3 secretion by TNBC cells. Downregulation of fibulin-3 in TNBC
cells impaired KP-10-induced cell migration and invasion. Mechanistically, fibulin-3
was found to regulate TNBC cell invasion via ERK1/2 and MMP-9-dependent pathway, downstream
of KISS1R activation ([Fig. 3]).
It is well known that KISS1 mRNA levels are highly expressed in the placenta and plasma kisspeptin levels soar
during pregnancy and remain elevated until parturition.[87]
[88]
[89] Rasoulzadeh and colleagues examined the effect of placental-derived kisspeptin on
breast cancer cell adhesion and invasion.[77] They collected conditioned media from human placental cells obtained from 11 placenta
from healthy women with term pregnancy and undergoing Cesarean delivery. They found
that placental-derived kisspeptins had a differential effect on TNBC (MDA-MB-231)
cells compared with ERα-positive breast cancer (MCF-7) cells. In MDA-MB-231 cells,
placental kisspeptins selectively reduced cell adhesion and promoted cell migration
and invasion, which was inhibited upon treatment of cells with the KISS1R antagonist,
P-234. In contrast, treatment of MCF-7 cells with placental kisspeptins had no effect
on cell adhesion or invasion. Mechanistically, the study showed that placental kisspeptins
increased MMP-9 expression and activity in MDA-MB-231 cells to thereby regulate cell
invasion. This corroborates findings from previous studies that kisspeptins can differentially
modulate invasiveness of breast cancer cells, depending on the ERα status.
Interestingly, KISS1 has been shown to function downstream of TGF-β to promote cell
invasion in TNBC[76] ([Fig. 4]). Tian et al showed that TGF-β signaling via Smad2/p21 induced high expression of
KISS1 in TNBC cells (MDA-MB-231 and SCP2) in contrast to ERα-positive (MCF-7) breast
cancer cells.[76] Downregulation of KISS1 blocked TGF-β-induced TNBC invasion by stimulating MMP-9
expression and activity. The authors examined KISS1 gene expression in 1,215 human breast tumors classified by ER status using the Cancer
Genome Atlas (TCGA) database and observed higher KISS1 expression in the aggressive basal-type, ERα-negative tumors versus the less aggressive
ER-α-positive tumors. Furthermore, using immunohistochemical analysis of KISS1 protein
expression in a tumor microarray composed of normal breast tissue and breast carcinoma
tissue from 48 patients, the study reported that positive lymph node status is associated
with a higher KISS1 levels. Further studies are required to determine how this links
with survival outcome and by what mechanisms TGF-β regulates KISS1 expression and
whether KISS1R is involved in this pathway.
Fig. 4 Transforming growth factor-β (TGF-β) promotes TNBC invasion via KISS1. TGF-β signaling
via Smad2/p21 induces KISS1 expression, to promote TNBC invasion in an ERK/MMP-9-dependent
manner. ERK, extracellular signal–regulated kinase; MMP-9, matrix metalloproteinase-9.
KISS1/KISS1R: Drug Resistance
KISS1/KISS1R: Drug Resistance
TNBC patients have a lower survival rate following initial response to chemotherapy
because tumors tend to develop chemoresistance and this limits the available options
for previously treated patients.[90]
[91] KISS1R signaling has been shown to induce chemoresistance in TNBC cells and multiple
ERα-negative breast cancer cells by two mechanisms.[65] First, KISS1R modulates the expression of the ATP-binding cassette drug efflux transporter,
breast cancer resistance protein (BCRP), a major multidrug-resistant transporter in
TNBC.[92]
[93] Second, KP-10 treatment of cells activates the tyrosine kinase, AXL,[65] a binding partner of EGFR that is highly expressed in TNBC.[94]
[95] AXL signaling is known to induce EMT as well as drug resistance[96]
[97] and AXL inhibitors are currently in clinical trial in various cancers.[98]
[99]
[100] KISS1R induces AXL transcription via enhanced binding of Sp1 to the AXL promoter.
Knockdown of AXL using siRNA decreased the expression of EMT markers, but did not
decrease BCRP expression, suggesting that KISS1R promotes drug resistance via two
independent mechanisms. KISS1R overexpressing cells displayed reduced accumulation
of the chemotherapeutic drug, doxorubicin, and displayed resistance to apoptosis as
evidenced by a reduction of cleaved PARP, which occurs in the onset of apoptosis.
In fact, KISS1R signaling promoted tumor cell survival by enhancing the expression
of cell survival molecules such as AKT, ERK, and the antiapoptotic protein, survivin.[65] Depletion of AXL or antagonizing KISS1R signaling resensitized tumor cells to chemotherapy.
Although the mechanisms by which KISS1R activates AXL are to be determined, this study
revealed that KISS1R is a key regulator of TNBC drug resistance.
In a study of human head and neck squamous cell carcinoma (HNSCC), KISS1 has been
shown to regulate drug resistance to the chemotherapeutic agent, cisplatin.[101] In this cancer, KISS1 functions as a metastasis suppressor and thus, KISS1 expression is lost in patients with metastatic tumors compared with nonmetastatic
tumors. The authors observed a profound decrease in KiSS1 mRNA expression in the cisplatin-resistant cell lines compared with the parental
cells, but there was no change in KISS1R expression. Depletion of KISS1 by siRNA in the parental HNSCC cells induced resistance to cisplatin. Conversely,
overexpression of KISS1 in HNSCC cells increased sensitivity of cisplatin-resistant cells to the chemotherapeutic
in addition to inhibiting cell migration and proliferation. Importantly, using two
preclinical xenograft models where human cells were injected into immunocompromised
mice, the study showed that reexpression of KISS1 in human cisplatin-resistant HNSCC cells decreased metastasis. Although the authors
do not address the mechanism regulating the loss of KISS1 in HNSCC, this study clearly revealed a role for KISS1 in inhibiting cisplatin drug resistance as well as metastasis in HNSCC.
Conclusions and Future Perspective
Conclusions and Future Perspective
Metastasis, the leading cause of cancer-related death, remains a major impediment
for the treatment of cancer[102] and several new therapeutic approaches are being investigated including targeting
the tumor microenvironment, mitophagy, and immune therapy.[103]
[104]
[105] In contrast to its original classification as a metastasis-suppressor gene in melanoma,
this review provides information as to the state of our current knowledge on the proinvasive
roles of KISS1 in breast cancer.
Understanding the role of the KISS1/KISS1R pathway in regulating TNBC metastasis and
drug resistance is still in its early period. Studies using preclinical xenograft
models as well as patient-derived xenografts are required for a better understanding
of the underlying molecular mechanisms by which KISS1R regulates cell invasion and
whether targeting this pathway inhibits TNBC metastasis and drug resistance in vivo.
Questions that remain to be answered include how does KISS1R communicate with other
receptors such as growth factor receptors (e.g., TGF-β and AXL) and what role does
KISS1R signaling play in other ERα-negative breast cancer subtypes (e.g., HER2-positive
tumors).
Traditionally, the epigenetic regulation of gene expression in cancer is considered
to be mediated via the inactivation of expression of tumor suppressor genes. Indeed,
in colorectal and bladder cancer where KISS1 functions as a tumor suppressor, KISS1 expression is decreased in primary tumors due to epigenetic modifications.[16] Recently, it is surfacing that epigenetic de-repression mechanisms such as DNA and
histone demethylation are at play resulting in the overexpression of some oncogenes
or cancer promoting genes in cancer and these can initiate cancer development and
make tumors more aggressive and resistant to treatment.[106]
[107]
[108] KISS1 expression is elevated in patient TNBC primary tumors; however, whether KISS1 is epigenetically regulated or undergoes miRNA regulation that results in changes
in regulatory elements in TNBC needs further investigation.
In summary, biomarker identification to guide treatment decisions in TNBC is an unmet
need, and an improved understanding of the molecular pathways that are deregulated
in the early stages of TNBC can provide opportunities for targeted drug therapeutic
intervention. TNBC cells overexpress KISS1 and secrete kisspeptin; however, it is
yet to be determined whether plasma kisspeptin levels are altered in TNBC patients
and whether this could serve as a potential biomarker for monitoring metastasis and
disease recurrence. Despite the need for further investigations, it remains abundantly
clear that KISS1/KISS1R plays important roles in TNBC invasion, metastasis, and drug
resistance and this pathway represents a novel drug target.
