Int. J. Biol. Sci. 2021, Vol.

17 2069

Ivyspring
International Publisher
International Journal of Biological Sciences
2021; 17(8): 2069-2079. doi: 10.7150/ijbs.60631
Review

Progress of Breast Cancer basic research in China

Xuerong Wang1#, Chao Wang2#, Jiaheng Guan3#, Baoan Chen3, Lin Xu2 and Ceshi Chen4
1. Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
2. Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China.
3. Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
4. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of
Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.

#These authors contribute equally to this work.

 Corresponding authors: Ceshi Chen, Ph.D, E-mail: chenc@[Link]; Tel: +86-871-65181944; Fax: +86-871-65181945; Lin Xu, M.D, E-mail:
xulin_83@[Link]; Tel: +86-25-83283571; Fax: +86-25-83641062.

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([Link]
See [Link] for full terms and conditions.

Received: 2021.03.19; Accepted: 2021.04.28; Published: 2021.05.11

Abstract
Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and
worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of
cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese
investigators have recently made new discoveries in basic breast cancer researches, especially regarding
cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper
understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic
targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this
review, we summarized the latest important findings in this field in China.
Key words: breast cancer; cancer stem cells; tumor microenvironment; metastasis; drug resistance

Introduction
Breast cancer is the most common malignant metastasis [6, 7]. Great advances in cancer cell-of-
disease in women worldwide. According to the data origin, somatic mutation, epigenetic alteration, and
released in 2019, breast cancer accounted for 30% of tumor microenvironment were revealed in recent
newly diagnosed malignant tumors in females, and studies, both basic and clinical, leading to a better
led to 15% of female deaths from cancer [1]. The understanding of the mechanism, the pathogenesis,
incidence and mortality of breast cancer are still the diagnosis, and the treatment of breast cancer.
rising, both in developing and developed countries Particularly, Chinese investigators have made great
[2]. In China, breast cancer morbidity and mortality achievements in cancer stem cells, microenvironment,
rank first among malignant diseases in females. Death metastasis, drug resistance, tumor biomarkers, and
rate reached about 6.9% among all female malignant new targets, as well as drugs for breast cancer
tumors [3]. The lack of early-stage screening and therapy. In this review, we summarized the important
detection methods and cost-effective therapies makes findings on breast cancer basic research in China from
breast cancer as one of the most severe disease burden 2019 to 2020.
globally [4]. According to the international consensus
guideline, the current treatment for breast cancer Cancer stem cells (CSCs)
mainly included chemotherapy, radiotherapy, CSCs are defined as a group of undifferentiated
targeted therapy, immunity therapy, and endocrine cells that possess properties of self-renewal and
therapy before and after surgery [5]. Nowadays, pluripotent differentiation. Although breast cancer
therapies targeted to cancer stem cells have been a hot stem cells (BCSCs) make up only a small
spot in breast cancer treatment, which is a supplement subpopulation within tumors, they are responsible for
to the traditional chemotherapeutic drugs that are tumor initiation, recurrence, metastasis, and therapy
unable to eradicate tumor dissemination and resistance [8]. Previous studies revealed a panel of

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biomarkers for BCSCs identification, among which promote the stemness of breast cancer cells in a
CD44high, CD24low and aldehyde dehydrogenase 1 cell-cell contact dependent manner (Fig. 1) [15]. In
(ALDH1)+ were the most commonly used biomarkers addition, the Jag1 expression in endothelial cells
[9]. Triple-negative breast cancer (TNBC) contains activates Notch 1 to upregulate Zeb1 expression and
more BCSCs than other subtypes, which is associated to increase vascular endothelial growth factor A
with worse outcomes [10, 11]. In 2019, protein C (VEGFA) production. In turn, VEGFA induces Jag1
receptor (PROCR) was identified as a novel marker expression in endothelial cells. Thus, the positive
for BCSCs, which could stratify TNBC into clinically feedback loop in the tumor perivascular niche
relevant subgroups and be a therapeutic target (Fig. 1) promotes the stemness of breast cancer cells [16].
[12]. NOTCH4 receptor was not only implicated in the There are other pathways to enhance the
regulation of BCSCs in TNBC, but also regarded as a stemness of BCSC. Activated interleukin-1 receptor
better marker for BCSCs than CD24-CD44+ in 2020 type 2 (IL1R2) interacts with deubiquitinase USP15
(Fig. 1). Mechanistically, NOTCH4 drives (ubiquitin-specific protease 15) to induce
mesenchymal-like BCSCs into a quiescent state and deubiquitination and stabilization of BMI1, which
induces epithelial-mesenchymal transition (EMT) via facilitates the self-renewal of BCSCs (Fig. 1) [17].
upregulating GAS1 and SLUG, respectively. Zhou et BCSCs were also promoted by SGCE via an
al. also demonstrated the importance of NOTCH4- interaction with c-Cbl and the inhibition of c-Cbl-
SLUG-GAS1 circuit in maintaining mesenchymal-like mediated epidermal growth factor receptor (EGFR)
BCSCs [13]. lysosomal degradation (Fig. 1) [18]. The elevated
Tumor microenvironment (TME) plays an stress sensor in response to hypoxia, Tribble 3 (TRIB3)
essential role in regulating the activity of BCSCs [14]. promoted BCSCs through AKT1-FOXO1 (forkhead
Tumor-associated macrophages (TAMs) with box O1)-SOX2 (sry-related high mobility box 2) axis
elevated LSECtin expression interacts with its [19]. Phospholipid scramblase 1 (PLSCR1) enhanced
receptor BTN3A3, expressed in cancer cells, to stem cell-like properties through upregulating signal

Figure 1. Schematic diagram of BCSCs and TME. (1) PROCR is a marker of BCSCs for stratifying TNBC into subgroups. (2) NOTCH4 is also a marker for BCSCs, driving
ML-BCBCs into a quiescent state via GAS1 and inducing EMT via SLUG. (3) TAMs with elevated LSECtin expression interacts with BTN3A3, promoting the stemness of breast
cancer cells. (4) The following pathways increase cell stemness. IL1R2 interacts with USP15 to induce deubiquitination and stabilization of BMI1. SGCE stabilizes EGFR. TSPAN-8
enhances stemness genes, including NANOG, OCT4, and ALDHA1. SH3RF3 activates PTX3 via the JNK-JUN pathway. (5) BCSCs are divided into e-BCSCs and q-BCSCs.
SETD4 is important in the maintenance of qBCSCs. (6) A positive feedback loop between CCL5-CCR5 and CCL18-PIPTNM3 is shown. TAMs secret CCL18, binding to
PIPTNM3 on breast cancer cells. Then breast cancer cells secret CCL5, inducing macrophages to a TAM-like phenotype CCR5. (7) Alisertib eliminates tumor-promoting MDSCs
and TAMs to reshape the immune microenvironment.

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transducer as well as activator of transcription 1 of HIF-1α-stabilizing long noncoding RNA (HISLA).

(STAT1) expression in basal-like breast cancer (BLBC) Reciprocally, lactate released from glycolytic cancer
[20]. Additionally, loss of SIRT4 promoted cells upregulates HISLA in TAMs, constituting a feed-
self-renewal and expansion of BCSCs through forward loop between TAMs and cancer cells [30].
suppressing glutamine metabolism in mitochondrial Psychological factors induced metabolic
and SIRT1-mediated BRCA1 transcription in nucleus, alterations was revealed to cancer progression.
which provided a novel cross-talk between Lactate dehydrogenase A (LDHA) executes the final
mitochondrial and nuclear sirtuins [21]. step of the Warburg effect by converting pyruvate to
Signaling pathways activated in BCSCs mainly lactate. Breast cancer stem-like properties can be
include Wnt, Notch, and Hedgedog (Hh) [22]. The Hh promoted by chronic stress-induced epinephrine via
signaling pathway is activated by the binding of Hh LDHA-dependent metabolic rewiring. Interestingly,
ligands, such as Sonic Hedgehog (SHH), and their vitamin C may reverse the chronic stress-induced
cognate receptors, such as Ptch1. Tetraspanin-8 cancer stem-like phenotype [31].
(TSPAN-8) recruits the ATXN3 deubiquitinating
enzyme to reduce the ubiquitination of PTCH1 and to Tumor microenvironment (TME)
inhibit the degradation of the SHH/PTCH1 complex The TME of breast cancer is composed of
(Fig. 1). Therefore, TSPAN8 enhances the Hh pathway multiple stromal cells, soluble factors, and physical
and breast cancer cell stemness [23]. In addition, SH3 properties, including intratumor and metastatic
domain containing ring finger 3 (SH3RF3) promotes microenvironment representing local and distant
BCSCs by activating the JNK (c-Jun N-terminal lesions, respectively [32].
kinase)-JUN pathway, as well as the expression of In malignant phyllodes tumors (PT), TAMs
pentraxin 3 (PTX3) (Fig. 1) [24]. promote malignant progression by secreting large
BCSCs are divided into two categories according amount of CCL18, which then binds to its receptor
to the cell cycle rate: energetic BCSCs (e-BCSCs) [25] PIPTNM3 on myofibroblasts [33]. Reciprocally,
and quiescent BCSCs (q-BCSCs) [26]. Q-BCSCs play malignant PT recruits and induces macrophages to a
critical roles in resistance to chemoradiotherapy and TAM-like phenotype by secreting CCL5. Thus, a
disease relapse. SET domain-containing protein 4 positive feedback loop between CCL5-CCR5 and
(SETD4) is important in the maintenance of qBCSCs CCL18-PIPTNM3 is constituted, which represents the
(Fig. 1). SETD4 facilitates heterochromatin formation communication of myofibroblasts with TAMs and
via H4K20me3 (trimethylation of lysine 20 of histone plays a central role in tumorigenesis of PT (Fig. 1) [34].
4) catalysis on certain promoter regions which leads to Tumor development is accompanied by the
the silencing of qBCSCs-suppressing genes. Notably, occurrence and persistence of immunosuppressive
SETD4-defined qBCSCs maintain quiescent state by microenvironment. Myeloid-derived suppressor cells
asymmetric division, producing a small qBCSC and a (MDSCs) and TAMs interact with CD4+ and CD8+ T
big active daughter cell; the latter generates normal lymphocytes and subsequently attenuate the
cancer cells [27]. These findings on stem cell status anti-tumor immunity response, which is one of the
expanded our knowledge on the epigenetic factors that most responsible for immune evasion.
determinants of q-BCSCs and provided new Alisertib, a selective Aurora A kinase inhibitor, could
therapeutic targets for drug-resistant q-BCSCs. reshape the immune microenvironment through
selectively eliminating tumor-promoting myeloid
Metabolism cells, including MDSCs and TAMs, as well as
Altered metabolism is an emerging hallmark of restoring the anti-tumor immunity of T lymphocytes
cancer. Unlike normal cells, cancer cells prefer aerobic (Fig. 1). Intriguingly, combining alisertib with anti-
glycolysis, which is accompanied by increased lactate programmed cell death-ligand 1 (PD-L1) therapy
production, also known as the Warburg effect [28]. showed a synergistic efficacy in the treatment of
Based on the law of conservation of electrons in advanced breast cancer [35].
chemical reactions, Li et al. built up an electron According to the “seed and soil” theory,
balance model to outline metabolic plasticity under premetastatic niches in destination organs are key
hypoxia. According to the model, both proline driving force for tumor dissemination and
biosynthesis and lipogenesis can act as alternative colonization [36]. Additionally, primary tumor is
electron acceptor. Blocking them synergistically capable of inducing B cell accumulation in draining
suppresses tumor growth [29]. Moreover, tumor lymph nodes. These tumor-educated B cells produce
associated macrophages (TAMs) enhance aerobic pathogenic IgG that targets the tumor membrane
glycolysis and induce apoptosis resistance of breast antigen HSPA4 (heat shock protein family A member
cancer cells via extracellular vesicle (EV) transmission 4) to activate the HSPA4-binding protein ITGB5

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(integrin β5) and the downstream Src/NF-κB FOXF2 deficiency BLBC tended to transdifferentiate
pathway. These findings illustrated the role of B cells to a myofibroblast/cancer associated fibroblast
in promoting the establishment of premetastatic (CAF)-like phenotype and metastasized to visceral
niches in draining lymph nodes and accelerating organs. The underlying mechanism involves the
breast cancer lymph node metastasis [37]. reciprocal repression loop between FOXF2 and
transforming growth factor-β (TGF-β) (Fig. 2) [39].
Tumor metastasis These groundbreaking studies provided theoretical
Distant metastasis is the main cause of breast basis for preventing breast cancer metastasis.
cancer related death. A recent study deepened our Metastasis-initiating cells (MIC) are a tiny
understanding of EMT in metastasis by revealing that population of cells, estimated less than 0.02% of
breast cancer cells were capable of recapitulating disseminated tumor cells, and are responsible for
various epithelial and mesenchymal phenotypes. forming secondary tumors. Yang et al found
Epithelial-type circulating tumor cells (CTCs) and platelet-derived growth factor receptor (PDGFR)
disseminated tumor cells (DTCs) with a restricted inhibition blocked AKT activation but not serum and
mesenchymal transition show the most metastatic glucocorticoid induced kinase 1 (SGK1) signaling in
traits, whereas mesenchymal-type CTCs and DTCs MIC, which resulted in suppressing lung metastasis of
display limited metastatic ability [34]. Bone is the breast cancer; however, primary tumor burden was
most common site of distant metastasis. To further not affected. Co-targeting PDGFR and SGK1 showed
explain the mechanisms underlying the predilection synergistic anti-cancer effects and led to further
of bone metastasis has always been a focus of breast inhibition of pulmonary metastases and primary
cancer research. It was proved that Forkhead box F2 breast tumors [40]. Reduction of cell–cell adhesion is
(FOXF2) regulated the epithelium-to-osteomimicry crucial for cancer cells departing from the primary
transition (EOT) via pleiotropic transactivation of the tumor. AMP-activated protein kinase (AMPK) is well
BMP4/SMAD1 signaling pathway and bone-related known for maintaining energy homeostasis. A recent
genes (BRGs), thus giving the metastatic tendency to study revealed that PI3K and HER2 activation
bone (Fig. 2) [38]. The same group also revealed that transcriptionally downregulated AMPKα1 expression

Figure 2. Schematic diagram of metastasis. (1) Mechanism of bone metastasis is shown.FOXF2 overexpressed by BLBC/luminal regulates EOT via BMP4/SMAD1 pathway
and BRGs, leading to bone metastasis. (2) Mechanism of visceral metastasis is shown. Deficiency of FOXF2 in BLBC transdifferentiates to myofibroblast/cancer associated fibroblast
(CAF)-like phenotype and metastasizes to visceral organs via TGF-β/SMAD/miR-182-5p, which in turn repress FOXF2. (3) PI3K and HER2 activation downregulates AMPKα1
expression via ΔNp63α, reducing cell-cell adhesion. (4) S100A14 promotes cancer metastasis by upregulating the secretion of CCL2 and CXCL5 via NF-κB pathway. (5)
Mechanisms of lncRNA in regulating TNBC metastasis are shown below. Oncogenic lncRNA, NAMPT-AS activates NAMPT via POU2F2 [Link] reduction of
LINC00665 encoded CIP2A-BP increases PI3K/AKT/NFκB to reduce lung metastasis. LINC00908 encodes ASRPS inhibits angiogenesis via VEGF.

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via ΔNp63α and highlighted that transcriptional activating aldolase A and ERK signaling pathway,
control was another layer of AMPK regulation, which thereby inhibiting the nucleotide metabolism and
suggested the pivotal role of AMPKα1 in cell-cell DNA damage caused by chemotherapy in breast
adhesion and cancer metastasis (Fig. 2) [41]. S100 cancer [50]. Additionally, Zhang et al revealed that a
calcium binding protein A14 (S100A14) promoted feed-forward circuit between serglycin (SRGN) and
cancer metastasis by upregulating the expression and YES-associated protein (YAP) induced HDAC2
secretion of CCL2 and CXCL5 via RAGE/NF-κB expression, promoting chemoresistance to 5-FU [51].
pathway (Fig. 2) [42]. These findings provided new Dong et al. found glutathione S-transferases P1
therapeutic strategies for inhibiting breast cancer (GSTP1) contributed to adriamycin resistance [52]. In
metastasis. TNBC, synaptotagmin-like 4 (SYTL4) contributes to
Long noncoding RNA (lncRNA) plays an taxane resistance via attenuating the stability of
important role in regulating TNBC metastasis. microtubule network and increasing the growth rate
Antisense strand of nicotinamide phosphoribosyl- of microtubule [53] The antisense intronic lncRNA
transferase (NAMPT-AS) was an oncogenic lncRNA (ai-lncRNA) EGOT (eosinophil granule ontogeny
that epigenetically activated NAMPT to promote transcript) sensitizes breast cancer cells to paclitaxel
breast cancer metastasis (Fig. 2) [43]. LncRNA by enhancing autophagy[54]. MEF2-interacting
LINC00665, encoding a micropeptide CIP2A-BP transcriptional repressor (MITR), as a truncated
(CIP2A binding peptide), significantly reduced lung isoform of HDAC9, induces resistance of paclitaxel
metastasis of breast cancer (Fig. 2) [44]. LncRNA via increasing interleukin-11 (IL11) expression and
LINC00908, encoding a polypeptide ASRPS (a small subsequent activating JAK/STAT3 signaling pathway
regulatory peptide of STAT3), inhibits angiogenesis [55].
and metastasis of TNBC (Fig. 2) [45]. In terms of endocrine therapy, antiestrogens
In addition, Nie et al. raised new precautions in stabilize MORC2 in a GPER1 (G protein coupled
dexamethasone therapy for breast cancer patients. estrogen receptor 1) dependent manner and decrease
Glucocorticoids (GCs) could activate TEA domain MORC2 enhanced cellular sensitivity to tamoxifen
transcription factor 4 (TEAD4) in the Hippo signaling and fulvestrant [56]. In estrogen receptor (ER)
pathway for cancer metastasis and chemo-resistance positive breast cancer, lncRNA BDNF-AS, driven by a
by enhancing the interaction of the glucocorticoid MEF2A regulated enhancer, induces endocrine
receptor (GR) with TEAD4 to form a transcriptional resistance of breast cancer by activating the RNH1
complex (Fig. 2) [46]. (ribonuclease inhibitor 1)/TRIM21/mTOR
(mechanistic target of rapamycin) cascade [57]. This is
Drug resistance a novel mechanism other than the canonical PI3K
Drug resistance, both intrinsic and acquired, (phosphatidylinositol-3-kinase)/AKT/mTOR axis.
remains the main obstacle for effective anticancer LncRNA DILA1 contributes to tamoxifen resistance in
therapies. breast cancer via interacting with Cyclin D1 and
In terms of chemotherapy, cancer cells can blocking its phosphorylation and degradation [58].
develop drug resistance by activating DNA damage Ajuba recruits DBC1 and CBP/p300, forming a
repair signaling pathways [47]. Following DNA ternary complex, to increase transcriptional activity of
damage, poly ADP-ribose polymerase 1 (PARP1) ERα and to potentiate the ERα target gene expression,
recruits MORC2 (MORC family CW-type zinc finger thereby contributing to tamoxifen resistance [59].
2) to DNA damage sites and catalyzes MORC2 MiR-575 enhances ERα activity and tamoxifen
PARylation, which enhances its chromatin resistance via targeting cyclin dependent kinase
remodeling activities, thereby facilitating efficient inhibitor 1B (CDKN1B) and BRCA1 [60]. Moreover,
DNA repair. In turn, MORC2 stabilizes PARP1 inactivation of neddylation with MLN4924
through a crosstalk between N-acetyltransferase transcriptionally inhibits ERα and significantly
(NAT10)-mediated acetylation and CHFR-mediated improves the fulvestrant sensitivity [61]. However, in
ubiquitination [48]. DNA-damaging chemo- ER negative breast cancer, targeting ubiquitin
therapeutic agents stimulate MORC2 acetylation in a carboxyl terminal hydrolase-L1 (UCH-L1)
NAT10 dependent manner, then acetylated MORC2 upregulates ERα expression via enhancing
activates G2 DNA damage checkpoint, enhancing cell ubiquitination and degradation of EGFR, and
survival following DNA damage [49]. Therefore, subsequently increases the sensitivity of tamoxifen
depleting MORC2 or inhibiting NAT10 sensitizes and fulvestrant [62].
cancer cells to chemotherapy by abrogating DNA In terms of targeted therapy, lncRNA TINCR
damage repair. Moreover, Rac 1 enhances the activity induces trastuzumab resistance by regulating
of non-oxidative pentose phosphate pathway via miR-125b/HER-2 (human epidermal growth factor

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receptor 2) pathways [63]. LncRNA TROJAN with LC3B expression and CD8+ T cells in TNBC
promotes ER+ breast cancer resistance to palbociclib, patients. Inhibition of TNC in autophagy impaired
a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, TNBC cells sensitizes T cell mediated tumor killing
through TROJAN-NKRF-CDK2 axis [64]. PARP and boosts anti-tumor effects of anti-PD-1/PD-L1
inhibitor olaparib is effective in treating breast cancer therapy [69]. These findings provided new
patients with BRCA1 mutations. All-trans retinoic approaches to potentially combine immunotherapy
acid (ATRA) sensitizes BRCA1-proficient breast with molecular-targeting agents. These drug
cancer to PARP inhibition by inhibiting Pin1 and resistance mechanisms aforementioned are
destabilizing BRCA1, which could extend the use of summarized in Table 1 and Figure 3.
PARP inhibitors [65].
In regard to immunotherapy, breast cancers have Tumor biomarkers
poor response to immunotherapy because of poor The prognosis of breast cancer mainly depends
T-cell infiltration and heightened immuno- on early detection and intervention. Recently,
suppression within TME [66]. A low-dose vascular accumulated evidence indicates that circulating tumor
endothelial growth factor receptor 2 (VEGFR2) DNA (ctDNA) could be a sensitive and specific
blockade can increase immune cell infiltration and biomarker for monitoring breast cancer progression
upregulate programmed cell death protein-1 (PD-1) and predicting relapse in early-stage [70]. A study
expression on immune cells, thus sensitizing breast showed the positive detection rate of ctDNA in
cancer to a PD-1 blockade [67]. PARP1 suppresses early-stage breast cancer could reach 74.2%.
PD-L1 expression via interaction with nucleophosmin Moreover, positive ctDNA after surgery indicated
(NPM1), which abolishes the binding of NPM1 at the potential recurrence and remote metastasis [71].
PD-L1 gene promoter in TNBC. Olaparib elevates Serum LRP6 ectodomain (LRP6N) could be another
PD-L1 expression and leads to better anti-cancer promising metastatic diagnosis marker for its binding
efficacy in combination with the anti-PD-L1 antibody to CXCR4 and competitively preventing SDF-1/
[68]. In addition, as a strong candidate for autophagy CXCR4-induced lung metastasis [72].
deficiency mediated immunosuppression, Tenascin-C
(TNC) is overexpressed and is inversely correlated

Table 1. Drug resistance mechanisms of breast cancer

Drug resistance Drugs Mechanism Reference
Chemotherapy DNA damage A feedback loop between MORC2 and PARP1 facilitates efficient DNA repair 48
agents NAT10-mediated MORC2 acetylation contributes to DNA damage-induced G2 checkpoint activation 49
Rac1 promotes the glycolysis, especially non-oxidative pentose phosphate pathway and nucleoside metabolism 50
5-FU A feed-forward circuit between SRGN and YAP induces HDAC2 expression to maintain stemness and 51
chemoresistance
adriamycin GSTP1 promotes autophagy by interacting with PI3K, p110α, and then preventing PI3K-Akt-mTOR pathway 52
signaling
paclitaxel SYTL4 decreases microtubule stability via inhibiting microtubule polymerization 53
EGOT enhances autophagosome accumulation via the upregulation of ITPR1 expression in cis and in trans 54
MITR increases IL11 expression and activation of downstream JAK/STAT3 signaling pathway 55
Endocrine tamoxifen/ Estrogen receptor antagonists stabilize MORC2 via the GPER1-PRKACA-CMA pathway 56
therapy fulvestrant UCH-L1 contributes to loss or reduction of ERα by the deubiquitinase-mediated stability of EGFR 62
tamoxifen BDNF-AS promotes RNH1 degradation via TRIM21-mediated ubiquitination and sustains the activation of mTOR 57
signaling
DILA1 blocks phosphorylation and degradation of Cyclin D1 58
Ajuba/DBC1/CBP/p300 ternary complex co-activates ERα transcriptional activity and enhances ERα acetylation 59
miR-575 enhances ERα activity by targeting CDKN1B and BRCA1 60
fulvestrant Inactivation of neddylation with MLN4924 inhibits ERα via delaying SGK degradation and inducing FOXO3a 61
nuclear export
Targeted therapy trastuzumab TINCR promotes HER-2 expression by sponging miR-125b and promotes EMT by targeting Snail-1 63
palbociclib TROJAN binds to NKRF and inhibits its interaction with RELA, upregulating the expression of CDK2 64
olaparib ATRA sensitizes BRCA1-proficient breast cancer to PARP inhibition by inhibiting Pin1 and destabilizing BRCA1 65
Immunotherapy anti-PD-1 Low-dose VEGFR2 blockade sensitizes tumors to anti-PD-1 67
therapy via upregulation of PD-1 on immune cells through stimulating the secretion of OPN and TGF-β
anti-PD-L1 PARP1 suppresses PD-L1 transcription through interacting with NPM1 and abolishing the binding of NPM1 at 68
the PD-L1 promoter
anti-PD-1/ TNC contributes to autophagy deficiencymediated immunosuppression via suppressing LC3B and CD8+ T cells 69
anti-PD-L1
PRKACA protein kinase cAMP-activated catalytic subunit alpha, CMA chaperone-mediated autophagy, SGK serum and glucocorticoid-induced protein kinase, FOXO3a
forkhead box O3a, OPN osteopontin.

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Figure 3. Schematic diagram of drug resistance. (A) The mechanism of drug resistance in chemotherapy, including DNA damage agents, 5-FU, Adriamycin, and paclitaxel.
(B) Drug resistance mechanism of tamoxifen/fulvestrant, tamoxifen and fulvestrant. (C) Drug resistance mechanism of trastuzumab, palbociclib and olaparib. (D) Drug resistance
mechanism of immunotherapy.

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Because of the highly heterogeneity of TNBC, database analysis. MPS1 (heterogeneous metabolic-
appropriate classification will provide effective pathway-based subtype 1) is the lipogenic subtype
prediction for outcomes. TNBC were classified into with upregulated lipid metabolism. MPS2 is the
three heterogeneous clusters based on the glycolytic subtype with upregulated carbohydrate
microenvironment phenotypes: cluster 1, the and nucleotide metabolism. MPS3 is the mixed
“immune-desert” cluster, with low microenvironment subtype with partial pathway dysregulation.
cells infiltration; cluster 2, the “innate immune- Different subtypes respond to metabolic inhibitors
inactivated” cluster, with resting innate immune cells with distinct sensitivity which enables the
and nonimmune stromal cells infiltration; and cluster development of personalized cancer therapy by
3, the “immune-inflamed” cluster, with abundant targeting unique metabolic profiles [76].
adaptive and innate immune cells infiltration. Cluster
1 and 2 were both called “cold tumors” while cluster 3 Novel therapeutic targets and new drugs
was a “hot tumor”. Immune checkpoint inhibitors With the increasing popularity of precision
might be effective for “immune-inflamed” clusters, therapy for breast cancer, it is urgent to develop new
indicating that these distinct phenotypes were therapeutic targets and drugs.
potential biomarkers for predicting therapeutic Recent studies showed the effects of FTO[77],
efficacy. The transformation of “cold tumors” into protein arginine methyltransferase 1 (PRMT1) [78],
“hot tumors” should also be considered when dealing coactivator associated arginine methyltransferase 1
with “immune-desert” and “innate immune- (CARM1)/PRMT4 [79], Otubain-2 (OTUB2) [80],
inactivated” clusters [73]. RING finger protein 144A (RNF144A) [81], plant
The molecular typing of breast cancer has been homeodomain finger protein 20-like protein 1
revealed deeply by novel detecting techniques. A (PHF20L1) [82], heat shock transcription factor 1
study divided Chinese TNBC into four subtypes (HSF1) [83], epithelial cell transforming sequence 2
based on multi-omics data: luminal androgen (ECT2) [84], pescadillo homolog 1 (PES1) [85],
receptor, immunomodulatory, basal-like immune- PHACTR2-AS1 (PAS1) [86], breast cancer-related
suppressed, and mesenchymal-like subtypes, which transcript 1 (BCRT1) [87], and circCDYL [88] on
could serve as a reference in order to further advance progression of breast cancer and they provided novel
the understanding and precision treatment of TNBC therapeutic targets. TNBC is especially hard to treat
[74]. Further, the same group conducted a phase Ib/II due to the lack of targets. A recent study
trial, demonstrating the clinical benefit of molecular demonstrated NOTCH1-ATR-CHK1 cascade and
subtyping-based and targeted sequencing-based cisplatin displayed good synergy in inhibiting TNBC
therapy for refractory metastatic TNBC. Specifically, by targeting cell cycle checkpoint, DNA damage, and
nab-paclitaxel in combination with anti-PD-1 therapy EMT [89]. In addition, TNBC progression was also
or with anti-VEGFR therapy showed favorable promoted by TROJAN [90], circSEPT9 [91], and
outcomes on IM (immunomodulatory) subtype and moesin (MSN) [92], which could be potent options for
BRCA1/2 wild type-BLIS (basal-like immune- this fatal disease. These potential novel therapeutic
suppressed) subtypes, respectively [75]. Moreover, targets are summarized in Table 2.
based on distinct metabolic dysregulation, TNBC was
classified into three subtypes via multi-omics

Table 2. Potential novel therapeutic targets of breast cancer

Target Function Mechanism Reference
PES1 Promotes breast cancer growth Forms a complex with TERT and the TR, regulating telomerase activity, telomere length 85
maintenance, and senescence
MSN Stimulates TNBC cells proliferation and Phosphorylated MSN interacts with the nucleoprotein NONO and promotes the nuclear 92
invasion localization of PKC interacting with MSN, which leads to the phosphorylation of CREB
and the up-regulation of downstream gene expression

PHF20L1 Maintains the proliferative state of breast recognizes H3K27me2 and collaborates with PRC2 and the NuRD complex in regulating 82
cancer cells H3K27 modifications to suppress a series of tumor suppressors
TROJAN Promotes TNBC cells proliferation and Increases ZMYND8 degradation and epigenetically upregulates metastasis-related genes 90
invasion
PAS1 Inhibits breast cancer cells proliferation and Binds to rDNA genes and recruits histone methyltransferase SUV39H1, triggering H3K9 86
metastasis methylation of these genes, resulting in the suppression of ribosome synthesis

BCRT1 Promotes breast cancer cells proliferation competitively binding with miR-1303 to protect PTBP3 from degradation; promotes M2 87
and mobility polarization; facilitates hypoxia-induced EMT
circCDYL Promotes breast cancer cells proliferation promotes breast cancer malignant progression via the miR-1275-ATG7/ULK1-autophagic 88
axis

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Int. J. Biol. Sci. 2021, Vol. 17 2077

Target Function Mechanism Reference

circSEPT9 Promotes TNBC cells proliferation, E2F1 and EIF4A3 mediated circSEPT9 regulates the expression of LIF via sponging 91
migration, invasion and inhibits TNBC cells miR-637 and activates LIF/Stat3 signaling pathway
apoptosis and autophagy
OTUB2 Promotes breast cancer stemness and EGF and KRAS mutation induce OTUB2 poly-SUMOylation, thereby deubiquitinates and 80
metastasis activates YAP/TAZ
NOTCH1 Induces the TNBC formation Promotes the EMT and regulates the cell cycle through activation of ATR-CHK1 signalling 89
pathway
PRMT1 Promotes breast cancer cells proliferation PRMT1-dependent methylation of C/EBPα promotes the expression of cyclin D1 by 78
blocking the interaction between C/EBPα and HDAC3
CARM1 Promotes ERα-positive breast cancer cells Transcriptional activates cognate estrogen-induced genes and methylates a large cohort of 79
proliferation proteins
FTO Promotes breast cancer cells proliferation, Demethylates N6-methyladenosine in the 3’UTR of BNIP3 and causes its degradation 77
colony formation and metastasis
RNF114A Suppresses breast cancer cells proliferation, Interacts with and targets HSPA2 for ubiquitination and degradation 81
colony formation, migration, and invasion
HSF1 Promotes breast cancer cells proliferation, PIM2-mediated HSF1 phosphorylation at Thr120 promotes proteostasis and 83
migration, and invasion carboplatin-induced autophagy, and enhances PD-L1 expression
ECT2 promotes breast cancer cells survival Forms a positive feedback loop with USP7 to promote stabilization of each other, 84
ultimately sustains the expression of MDM2
TERT telomerase reverse transcriptase, TR telomerase RNA, PKC protein kinase C, CREB cAMP response element–binding protein, PRC2 polycomb repressive complex 2,
NuRD Mi-2/nucleosome remodeling and deacetylase, ZMYND8 zinc finger MYND-type containing 8, rDNA ribosome DNA, LIF leukemia inhibitory factor, TAZ WW
domain-containing transcription factor, C/EBPα CCAAT/enhancer binding protein α, HSPA2 heat-shock protein family A member 2,PIM proviral integration site for
moloney murine leukemia virus.

As we know, tumor metabolism is important in numbers, limited treatment options, and

cancer progression. Nevertheless, the lack of effective unsatisfactory treatment efficacy in China,
and selective anti-metabolism drugs hinders clinical investigators focused on the exploration of drug
application. Chen et al reported a small molecule resistance and metastasis mechanisms and made great
ZY-444 bound to pyruvate carboxylase, which was a efforts to identify new tumor biomarkers and
key anaplerotic enzyme of the tricarboxylic acid cycle therapeutic targets in order to improve the diagnosis
in promoting cancer growth and metastasis through and treatment of breast cancer. However, there is still
Wnt/β-catenin/Snail signaling pathways. ZY-444 a lack of milestone discovery in terms of breast cancer
suppressed breast cancer cell proliferation with low cell origin, pathological typing, and targeted
cytotoxicity in normal cells by inactivating catalytic metastatic therapy. Thus, multi-party cooperation is
activity of pyruvate carboxylase [93]. Flubendazole, a strongly recommended to make a breakthrough in
broad-spectrum anthelmintic drug belonging to basic research and clinical translation.
benzimidazole group, has been repurposed as a
promising anti-cancer agent [94]. Zhen et al revealed Acknowledgements
flubendazole induced autophagic cell death by This work was supported by the National Key
targeting Eva-1 homolog A (EVA1A) and suppressed Research and Development Program of China
TNBC proliferation and migration [95]. Moreover, [2020YFA0112300 and 2018YFC2000400 to CC],
resistomycin, QN-1 and emodin attenuates TNBC National Natural Science Foundation of China
progression via binding to Pellino-1 to promote [81830087 and 31771516 for CC, 81972763 and
FBXO11-mediated SNAIL/SLUG degradation [96], 81473241 for XW, 81872378 for LX] and Jiangsu Social
down-regulating c-MYC transcription [97] and Development Project [BE2018711 for BC].
reducing VEGFA transcription [98], respectively.
Accordingly, these studies provided alternative Author contribution Statement
strategies for treating TNBC. CW and XW wrote the manuscript. CC, LX, JG
and BC conceived the study and edited the
Conclusion manuscript.
In summary, Chinese investigators have made
significant progress in all areas of breast cancer Competing Interests
research over the last two years, particularly in the The authors have declared that no competing
field of BCSCs. A number of new BCSC membrane interest exists.
biomarkers, including PROCR, NOTCH4, SGCE,
TSPAN8, and IL1R2, were identified. They may be References
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