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Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer

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Abstract

Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC), which shows immunohistochemically negative expression of hormone receptor i.e., Estrogen receptor and Progesterone receptor along with the absence of Human Epidermal Growth Factor Receptor-2 (HER2/neu). In Indian scenario the prevalence of BC is 26.3%, whereas, in West Bengal the cases are of 18.4%. But the rate of TNBC has increased up to 31% and shows 27% of total BC. Conventional chemotherapy is effective only in the initial stages but with progression of the disease the effectivity gets reduced and shown almost no effect in later or advanced stages of TNBC. Thus, TNBC patients frequently develop resistance and metastasis, due to its peculiar triple-negative nature most of the hormonal therapies also fails. Development of chemoresistance may involve various factors, such as, TNBC heterogeneity, cancer stem cells (CSCs), signaling pathway deregulation, DNA repair mechanism, hypoxia, and other molecular factors. To overcome the challenges to treat TNBC various targets and molecules have been exploited including CSCs modulator, drug efflux transporters, hypoxic factors, apoptotic proteins, and regulatory signaling pathways. Moreover, to improve the targets and efficacy of treatments researchers are emphasizing on targeted therapy for TNBC. In this review, an effort has been made to focus on phenotypic and molecular variations in TNBC along with the role of conventional as well as newly identified pathways and strategies to overcome challenge of chemoresistance.

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Abbreviations

BC:

Breast cancer

TNBC:

Triple-negative breast cancer

TN:

Triple-negative

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2/neu:

Human epidermal growth factor receptor-2

HR:

Hormone receptor

AR:

Androgen receptor

CSC:

Cancer stem cell

TP53/p53:

Tumor-suppressor protein-53

ITH:

Intra-tumor heterogeneity

LAR:

Luminal androgen receptor

M:

Mesenchymal

MSL:

Mesenchymal stem-like

IM:

Immunomodulatory

BL1:

Basal-like 1

BL2:

Basal-like 2

pCR:

Pathological complete response

NACT:

Neo-adjuvant chemotherapy

PI3K:

Phosphoinositol 3-kinase

PI3KCA:

Phosphoinositol 3-kinase CA

PAM:

PI3k/AKT/mTOR

PTEN:

Phosphatase and Tensin homolog

mTOR:

Mammalian target of rapamycin

AKT:

Ak strain transforming

INPP4B:

Inositol polyphosphate 4-phosphatase type II B

PARP:

Poly ADP ribose polymerase 1

BRCA1/2:

Breast cancer gene 1/2

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

Mabs:

Monoclonal antibodies

NGS:

Next-generation sequencing

BCCC:

Breast cancer cell clusters

ABC:

ATP-binding cassette

MRP:

Multidrug-resistant protein

BCRP:

Breast cancer resistance protein

TGF-β:

Transforming growth factor β

RTK:

Receptor tyrosine kinases

GSI:

G-protein specific inhibitor

Hh:

Hedgehog

PTCH:

Patched Hh

SMO:

Smoothened Hh

SHh:

Sonic Hedgehog

GLI:

Glioma-associated oncogene transcription factors

CCC:

Cadherin–Catenin-Complex

Wnt/β-catenin:

Wingless-related integration site 1 protein/Catenin β 1 protein

Nek2B:

NIMA-related kinase X

FZD6:

Frizzled family protein 6

LRP6:

Low-density lipoprotein receptor-related protein 6

LINP1:

Long noncoding RNA

CHEK2:

Cell cycle checkpoint kinase 2

TUFT1:

Tuftelin-1

Rac1:

Ras-related C3 botulinum toxin substrate 1

GTP:

Guanosine triphosphate

RelA:

REL-associated protein

DUSP1:

Dual specificity protein phosphatase 1

HIF1:

Hypoxia-induced factor-1

ECM:

Extracellular matrix

P4HA1:

Collagen prolyl 4-hydroxylase 1

α-KG:

Alpha-ketoglutarate

ROS:

Reactive oxygen species

C1QBP:

Complement 1q binding protein

PTX:

Paclitaxel

IC50:

Half-maximal inhibitory concentration

HMGA1:

High-mobility groupA1

AUR K A:

Aurora kinase A

MELK:

Maternal embryonic leucine zipper kinase

WT-p53:

Wild-type p53

RhoA:

Ras homolog family member A

IκB-α:

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha

MDM2:

Mouse double minute 2 homolog

pRB:

Retinoblastoma protein

RASSF1A:

Ras association domain family 1A

APC/Cdc20:

Anaphase-promoting complex/cell division cycle protein 20 homolog

FOXO:

Forkhead box O

YAP:

Yes-associated protein

MST1/2:

Macrophage-stimulating 1/2

LATS1/2:

Large tumor-suppressor kinase 1/2

TrCP:

Transducin repeat containing protein

SRGN:

Serglycin

ITGA5:

Integrin alpha-5 precursor protein

FAK:

Focal adhesion kinase

CREB:

CAMP response element-binding protein

TEAD-1:

Transcriptional enhanced associate domain-1

RUNX1:

Runt-related transcription factor-1

HDAC2:

Histone deacetylase-2

CD44+ :

Cell surface adhesion receptor 44+

CD24−:

Cell surface adhesion receptor 24−

CERK:

Ceramide kinase

C-1-P:

Ceramide-1-phosphate

SER:

Smooth endoplasmic reticulum

Raf:

Rapidly accelerated fibrosarcoma protein

MEK:

Mitogen activated protein kinase2

ERK:

Extracellular signal regulated protein kinase

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  1. Arijit Nath and Soham Mitra shares equal authorship.

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  1. Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, Odisha, 751024, India

    Arijit Nath

  2. Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, Odisha, 769008, India

    Soham Mitra

  3. Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700026, India

    Tanuma Mistry, Ranita Pal & Vilas D. Nasare

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Nath, A., Mitra, S., Mistry, T. et al. Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer. Med Oncol 39, 14 (2022). https://doi.org/10.1007/s12032-021-01610-x

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