TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy
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biomedicines Review TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy Desh Deepak Singh 1 and Dharmendra Kumar Yadav 2,* 1 Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur 303002, India; [email protected] 2 Department of Pharmacy and Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon 21924, Korea * Correspondence: [email protected]; Tel.: +82-32-820-4948 Abstract: Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer associated with a high rate of metastasis, poor prognosis, and lack of therapeutic targets. Although target-based therapeutic options are approved for other cancers, only limited therapeutic options are available for TNBC. Cell signaling and receptor-specific targets are reportedly effective in patients with TNBC under specific clinical conditions. However, most of these cancers are unresponsive, and there is a requirement for more effective treatment modalities. Further, there is a lack of effective biomarkers that can distinguish TNBC from other BC subtypes. ER, PR, and HER2 help identify TNBC and are widely used to identify patients who are most likely to respond to diverse therapeutic strategies. In this review, we discuss the possible treatment options for TNBC based on its inherent subtype receptors and pathways, such as p53 signaling, AKT signaling, cell cycle regulation, DNA damage, and programmed cell death, which play essential roles at multiple stages of TNBC development. Citation: Singh, D.D.; Yadav, D.K. We focus on poly-ADP ribose polymerase 1, androgen receptor, vascular endothelial growth factor TNBC: Potential Targeting of Multiple receptor, and epidermal growth factor receptor as well as the application of nanomedicine and Receptors for a Therapeutic immunotherapy in TNBC and discuss their potential applications in drug development for TNBC. Breakthrough, Nanomedicine, and Immunotherapy. Biomedicines 2021, 9, Keywords: triple-negative breast cancer; therapeutic target; signaling pathway; clinical trial 876. https://doi.org/10.3390/ biomedicines9080876 Academic Editors: Agata 1. Introduction Grazia D’Amico, Luca Vanella and Antonella Marino Gammazza Breast cancer (BC) is the most common type of cancer in women worldwide. The molecular classification of BC is shown in Figure1. The highest mortality rate has been Received: 15 June 2021 observed in triple-negative breast cancer (TNBC). TNBC is characterized by a high histo- Accepted: 21 July 2021 logical grade and proliferation rate and ductal histology and is associated with a lack of Published: 23 July 2021 estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression (making it ER-, PR-, and HER2-negative). The classification Publisher’s Note: MDPI stays neutral of TNBC is shown in Figure2[ 1]. Metastatic TNBC (mTNBC) is associated with a poor with regard to jurisdictional claims in overall survival rate [2]. TNBC has a high recurrence rate, which is the greatest within the published maps and institutional affil- first 3 years. However, a sharp reduction in recurrence is observed after 5 years. Therefore, iations. there is a lack of long post-therapy regimens [2,3]. Ductal pathology and gene expression analyses have led to further classification of BC into HER2-enhanced, luminal A and B, basal-like, and claudin-low subtypes [1,4]. The claudin-low subtype is primarily diagnosed in women under 45 years of age and is identified by a high expression of epithelial-to- Copyright: © 2021 by the authors. mesenchymal transition-associated genes, low expression of hormone receptor (HR), and Licensee MDPI, Basel, Switzerland. low expression of tight junction markers [5]. Currently, TNBC diagnosis is based on mam- This article is an open access article mography, immunohistochemistry, and radio-imaging. Confirmatory biopsy of metastatic distributed under the terms and lesions is required, as metastatic lesions possess different phenotypes based on the tumor conditions of the Creative Commons type [6]. Surgery is sometimes recommended to treat TNBC [7]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 876. https://doi.org/10.3390/biomedicines9080876 https://www.mdpi.com/journal/biomedicines BiomedicinesBiomedicines 2021, 9, 2021x FOR, 9 ,PEER 876 REVIEW 2 of 28 2 of 26 Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 28 Figure 1. FigureMolecular 1. classification of breast cancer. Figure 1.Molecular Molecular classificationclassification of of breast breast cancer. cancer. Figure 2. Classification of triple-negative breast cancer. FigureFigure 2. 2.Classification Classification of triple-negative breast breast cancer. cancer. TNBC hasTNBC TNBCbeen hasthe has beensubject been thethe of subjectsubjectintensive of of researchintensive intensive on research researchnew therapeutic on onnew new therapeutic approaches therapeutic approaches in approaches in in recent years [3]. The development of targeted cancer therapies, often in combination with recentrecent years years [3 [3].]. The The developmentdevelopment of of targeted targeted cancer cancer therapies, therapies, often often in combination in combination with with establishedestablished chemotherapy, chemotherapy, has been applied has been to applied a few new to a clinical few new studies clinical [8,9]. studies Therefore, [8,9]. Therefore, established chemotherapy, has been applied to a few new clinical studies [8,9]. Therefore, there is an thereurgent is needan urgent to develop need to novel develop ther novelapeutic ther options.apeutic Capeci options.tabine Capeci hastabine been hasused been used in combinationtherein iscombination an with urgent docetaxel, needwith to docetaxel, developixabepilone, novel ixabepilone, doxorubicin therapeutic doxorubicin options.cyclophosphamide, Capecitabinecyclophosphamide, and has been and used in paclitaxelcombination inpaclitaxel metastatic in with metastaticTNBC docetaxel, [1–8]. TNBC Many ixabepilone, [1–8]. studies Many doxorubicinhave studies been have performed cyclophosphamide, been performed to determine to anddetermine paclitaxel in whethermetastatic patientswhether with TNBCpatients TNBC [ 1with– 8were]. ManyTNBC more were studies like lymore to have choose like beenly tomastectomy performedchoose mastectomy over to determine lumpectomy over lumpectomy whether patients [7]. Resultswith[7]. revealed TNBC Results were that revealed morethe TN that likely status, the to TN choosewhile status, being mastectomy while associated being over associated with lumpectomy younger with youngerage [7 ].and Results age and revealed that the TN status, while being associated with younger age and higher-grade tumors, did not impact the patients’ choice of surgical treatment [5–7]. Although TNBC tends to be more aggressive, decision-making for surgery likely rests on more traditional clinicopathological variables and patient preferences in disputative TNBC [6]. Traditionally, radiotherapy Biomedicines 2021, 9, x FOR PEER REVIEW 3 of 28 Biomedicines 2021, 9, 876 3 of 26 higher-grade tumors, did not impact the patients’ choice of surgical treatment [5–7]. Alt- hough TNBC tends to be more aggressive, decision-making for surgery likely rests on ismore administered traditional inclinicopathological TNBC, as in other variables breast and cancer patient subtypes, preferences following in disputative mastectomy or conservativeTNBC [6]. Traditionally, breast surgery radiotherapy (CBS); however,is administered this issue in TNBC, remains as in controversialother breast cancer [10]. subtypes,As TNBC following is a mastectomy rapidly growing or conservative and locally breast aggressive surgery (CBS); cancer, however, CBS followed this issue by radia- tionremains therapy controversial in early [10]. stage (T N ) may not be equivalent to mastectomy as in other types As TNBC is a rapidly growing1–2 and0 locally aggressive cancer, CBS followed by radia- of BC [10]. Based on the results of metastatic lesion biopsies, TNBC-associated molecu- tion therapy in early stage (T1-2N0) may not be equivalent to mastectomy as in other types larof BC targets [10]. Based and their on the small results molecule of metastat inhibitorsic lesion biopsies, are shown TNBC-associated in Figure3. In molecular addition to the intrinsictargets and evolutional their small molecule drive in inhibitors TNBC, anticancer are shown treatmentin Figure 3. servesIn addition as a to source the intrin- of selection pressuresic evolutional [10,11 drive]. To in this TNBC, date, anticancer it remains trea controversialtment serves as whether a source chemotherapy of selection pres- resistance emergessure [10,11]. from To the this selection date, it andremains expansion controversial of rare whether pre-existing chemotherapy subclones resistance (adaptive resis- tance)emerges or from from the the selection induction and of expansion new mutations of rare pre-existing (acquired resistance)subclones (adaptive [11]. Currently, re- the treatmentsistance) or options from the for induction TNBC are of new limited, mutations because (acquired TNBC resistance) tumors are [11]. not Currently, sensitive tothe hormone therapytreatment and options TNBC-specific for TNBC are drug limited, targets because are TNBC lacking. tumors Some are common not sensitive chemotherapeutic to hor- agentsmone therapy show limited and TNBC-specific efficacy [2,6 drug,10,11 targ]. Therefore,ets