Review
. 2013 Jan; 138(1):21-35.
doi: 10.1007/s10549-013-2421-5.

Molecularly targeted therapies for metastatic triple-negative breast cancer

Soley Bayraktar 1 Stefan Glück  
Affiliations
  • PMID: 23358903
  •     62 citations

Abstract

Triple-negative breast cancer (TNBC) refers to a heterogeneous group of tumors that do not express the estrogen/progesterone-receptor (ER/PR), and human epidermal growth factor receptor-2 (HER2). TNBC is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapy regimens. There have been significant improvements in the outcome of other subtypes of breast cancer, including ER-positive/HER2 overexpressed tumors, attributed to the addition of targeted therapy, including hormonal agents and trastuzumab. However, no specific targeted agents are currently available for the treatment of TNBC. This review aims to collate and describe the most recent data on targeted therapies that have demonstrated efficacy in the management of metastatic TNBC. Targeted agents that have been investigated in the treatment of metastatic TNBC include inhibitors of poly(ADP-ribose) polymerase, angiogenesis, mammalian target of rapamycin, epidermal growth factor receptor, HDAC, Jak2, and Src. Several of these agents have shown considerable promise.

Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer.
A D'Anneo, D Carlisi, +9 authors, G Tesoriere.
Cell Death Dis, 2013 Nov 02; 4. PMID: 24176849    Free PMC article.
Evaluating many treatments and biomarkers in oncology: a new design.
Richard Kaplan, Timothy Maughan, +4 authors, Mahesh Parmar.
J Clin Oncol, 2013 Nov 20; 31(36). PMID: 24248692    Free PMC article.
Molecular profiling for breast cancer: a comprehensive review.
Muaiad Kittaneh, Alberto J Montero, Stefan Glück.
Biomark Cancer, 2013 Nov 20; 5. PMID: 24250234    Free PMC article.
Review.
Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of β-tubulin.
Marie L Antony, Joomin Lee, +12 authors, Shivendra V Singh.
J Biol Chem, 2013 Dec 04; 289(3). PMID: 24297176    Free PMC article.
Multidrug-resistant breast cancer: current perspectives.
Heather L Martin, Laura Smith, Darren C Tomlinson.
Breast Cancer (Dove Med Press), 2014 Mar 22; 6. PMID: 24648765    Free PMC article.
Review.
Meta-analysis on the association between pathologic complete response and triple-negative breast cancer after neoadjuvant chemotherapy.
Kunpeng Wu, Qiaozhu Yang, +2 authors, Zhixiong Yang.
World J Surg Oncol, 2014 Apr 16; 12. PMID: 24731479    Free PMC article.
Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer.
Christine Mehner, Alexandra Hockla, +3 authors, Evette S Radisky.
Oncotarget, 2014 May 09; 5(9). PMID: 24811362    Free PMC article.
Highly Cited.
Challenges in the Treatment of Triple Negative and HER2-Overexpressing Breast Cancer.
L Alexis Hoeferlin, Charles E Chalfant, Margaret A Park.
J Surg Sci, 2014 May 13; 1(1). PMID: 24818173    Free PMC article.
Mammary cancer chemoprevention by withaferin A is accompanied by in vivo suppression of self-renewal of cancer stem cells.
Su-Hyeong Kim, Shivendra V Singh.
Cancer Prev Res (Phila), 2014 May 16; 7(7). PMID: 24824039    Free PMC article.
Suicide HSVtk gene delivery by neurotensin-polyplex nanoparticles via the bloodstream and GCV Treatment specifically inhibit the growth of human MDA-MB-231 triple negative breast cancer tumors xenografted in athymic mice.
Rosa A Castillo-Rodríguez, Martha L Arango-Rodríguez, +4 authors, Daniel Martínez-Fong.
PLoS One, 2014 May 16; 9(5). PMID: 24824754    Free PMC article.
MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis.
Brock Humphries, Zhishan Wang, +5 authors, Chengfeng Yang.
Carcinogenesis, 2014 Jun 14; 35(10). PMID: 24925028    Free PMC article.
Visfatin promotes cell and tumor growth by upregulating Notch1 in breast cancer.
Hyun-Joo Park, Su-Ryun Kim, +4 authors, Soo-Kyung Bae.
Oncotarget, 2014 Jun 28; 5(13). PMID: 24970818    Free PMC article.
Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry.
Jong-Han Yu, Jong Won Lee, +12 authors, Sei-Hyun Ahn.
J Breast Cancer, 2014 Jul 12; 17(2). PMID: 25013433    Free PMC article.
Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.
Nicole M Davis, Melissa Sokolosky, +23 authors, James A McCubrey.
Oncotarget, 2014 Jul 23; 5(13). PMID: 25051360    Free PMC article.
Highly Cited. Review.
Curcumin restores sensitivity to retinoic acid in triple negative breast cancer cells.
Padmamalini Thulasiraman, Daniel J McAndrews, Imran Q Mohiudddin.
BMC Cancer, 2014 Sep 28; 14. PMID: 25260874    Free PMC article.
Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.
Todd A MacKenzie, Gary N Schwartz, +5 authors, Lorenzo F Sempere.
Am J Pathol, 2014 Dec 03; 184(12). PMID: 25440114    Free PMC article.
Combined phosphoproteomics and bioinformatics strategy in deciphering drug resistant related pathways in triple negative breast cancer.
Xinyu Deng, Morris Kohanfars, +4 authors, Helena R Chang.
Int J Proteomics, 2014 Dec 06; 2014. PMID: 25478227    Free PMC article.
Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells.
Z Wang, X Shi, +10 authors, D Ju.
Cell Death Dis, 2014 Dec 17; 5. PMID: 25501824    Free PMC article.
The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models.
Juan Garona, Marina Pifano, +7 authors, Daniel F Alonso.
Int J Oncol, 2015 Apr 08; 46(6). PMID: 25846632    Free PMC article.
Inhibition of SHP2 in basal-like and triple-negative breast cells induces basal-to-luminal transition, hormone dependency, and sensitivity to anti-hormone treatment.
Hua Zhao, Yehenew M Agazie.
BMC Cancer, 2015 Apr 18; 15. PMID: 25885600    Free PMC article.
HOXB5 Promotes the Proliferation and Invasion of Breast Cancer Cells.
Ji-Yeon Lee, Ho Hur, +4 authors, Myoung Hee Kim.
Int J Biol Sci, 2015 May 23; 11(6). PMID: 25999793    Free PMC article.
The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.
N C Hait, D Avni, +10 authors, S Spiegel.
Oncogenesis, 2015 Jun 09; 4. PMID: 26053034    Free PMC article.
The La-Related Proteins, a Family with Connections to Cancer.
Chara Stavraka, Sarah Blagden.
Biomolecules, 2015 Oct 27; 5(4). PMID: 26501340    Free PMC article.
Review.
SHP2 acts both upstream and downstream of multiple receptor tyrosine kinases to promote basal-like and triple-negative breast cancer.
Fatimah Matalkah, Elisha Martin, Hua Zhao, Yehenew M Agazie.
Breast Cancer Res, 2016 Jan 06; 18(1). PMID: 26728598    Free PMC article.
Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study.
Lori M van Roozendaal, Leonie H M Smit, +6 authors, Marjolein L Smidt.
Breast Cancer Res Treat, 2016 Mar 26; 156(3). PMID: 27013474    Free PMC article.
Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis.
D Carlisi, G Buttitta, +4 authors, G Tesoriere.
Cell Death Dis, 2016 Apr 15; 7. PMID: 27077810    Free PMC article.
Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-I/IGF-IR pathways in breast cancer.
Mohamad Elbaz, Dinesh Ahirwar, +2 authors, Ramesh K Ganju.
Oncotarget, 2016 May 24; 8(18). PMID: 27213582    Free PMC article.
Integrative exploration of genomic profiles for triple negative breast cancer identifies potential drug targets.
Xiaosheng Wang, Chittibabu Guda.
Medicine (Baltimore), 2016 Jul 30; 95(30). PMID: 27472710    Free PMC article.
The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells.
Javier A Menendez, Luciano Vellon, Ingrid Espinoza, Ruth Lupu.
Oncoscience, 2016 Oct 08; 3(7-8). PMID: 27713913    Free PMC article.
Photodynamic Therapy Mediated by Nontoxic Core-Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer.
Xiaopin Duan, Christina Chan, +3 authors, Wenbin Lin.
J Am Chem Soc, 2016 Dec 16; 138(51). PMID: 27976881    Free PMC article.
Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle.
Li Zhang, Nadimpalli Rs Varma, +3 authors, Meser M Ali.
J Nanomed Nanotechnol, 2016 Dec 27; 7(5). PMID: 28018751    Free PMC article.
A network meta-analysis on the efficacy of targeted agents in combination with chemotherapy for treatment of advanced/metastatic triple-negative breast cancer.
Long Ge, Yan Tang, +8 authors, Ke-Hu Yang.
Oncotarget, 2017 Sep 25; 8(35). PMID: 28938657    Free PMC article.
Network Modularity in Breast Cancer Molecular Subtypes.
Sergio Antonio Alcalá-Corona, Guillermo de Anda-Jáuregui, Jesús Espinal-Enríquez, Enrique Hernández-Lemus.
Front Physiol, 2017 Dec 06; 8. PMID: 29204123    Free PMC article.
VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin.
Yuhui Wang, Menglin Zhu, +5 authors, Xiaoqun Duan.
Molecules, 2018 Jan 11; 23(1). PMID: 29316690    Free PMC article.
A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer.
Zhixian Liu, Mengyuan Li, Zehang Jiang, Xiaosheng Wang.
Transl Oncol, 2018 Feb 08; 11(2). PMID: 29413765    Free PMC article.
Highly Cited.
c-Src inhibitor selectively inhibits triple-negative breast cancer overexpressed Vimentin in vitro and in vivo.
Longquan Lou, Ziyi Yu, +2 authors, Yi Zhao.
Cancer Sci, 2018 Mar 27; 109(5). PMID: 29575318    Free PMC article.
MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis.
Pranabananda Dutta, Marianna Sarkissyan, +2 authors, Jaydutt V Vadgama.
Breast Cancer Res Treat, 2018 Mar 30; 170(3). PMID: 29594759    Free PMC article.
Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON.
Zhiwei Hu, Rulong Shen, +6 authors, William E Carson.
Cancer Immunol Res, 2018 Apr 07; 6(6). PMID: 29622581    Free PMC article.
All-trans-retinoic acid activates the pro-invasive Src-YAP-Interleukin 6 axis in triple-negative MDA-MB-231 breast cancer cells while cerivastatin reverses this action.
Belén Mezquita, Pau Mezquita, +5 authors, Cristóbal Mezquita.
Sci Rep, 2018 May 08; 8(1). PMID: 29728589    Free PMC article.
Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine.
Minjee Kim, Sani H Kizilbash, +4 authors, William F Elmquist.
Pharm Res, 2018 Jul 14; 35(9). PMID: 30003344    Free PMC article.
Review.
Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer.
Nan Wu, Jinghua Zhang, +5 authors, Juntian Liu.
Oncol Lett, 2018 Sep 27; 16(4). PMID: 30250564    Free PMC article.
Review.
Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer.
Melissa A Maczis, Michael Maceyka, +8 authors, Sarah Spiegel.
J Lipid Res, 2018 Oct 14; 59(12). PMID: 30315000    Free PMC article.
TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer.
Mohamad Elbaz, Dinesh Ahirwar, +5 authors, Ramesh K Ganju.
Oncotarget, 2016 May 27; 9(71). PMID: 30323891    Free PMC article.
Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines.
Jason H Winnike, Delisha A Stewart, +2 authors, Susan J Sumner.
Int J Breast Cancer, 2018 Oct 27; 2018. PMID: 30363973    Free PMC article.
SRC inhibition prevents P-cadherin mediated signaling and function in basal-like breast cancer cells.
Ana Sofia Ribeiro, Ana Rita Nobre, +11 authors, Joana Paredes.
Cell Commun Signal, 2018 Nov 09; 16(1). PMID: 30404626    Free PMC article.
Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer.
Pingping Li, Can Zhou, +4 authors, Peijun Liu.
Clin Exp Pharmacol Physiol, 2019 May 16; 46(9). PMID: 31087799    Free PMC article.
TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway.
Weiguang Liu, Jianjun Han, +2 authors, Jianchao He.
Cancer Cell Int, 2019 Oct 02; 19. PMID: 31572059    Free PMC article.
Recent advances in nanotheranostics for triple negative breast cancer treatment.
Vikram Thakur, Rajaletchumy Veloo Kutty.
J Exp Clin Cancer Res, 2019 Oct 30; 38(1). PMID: 31661003    Free PMC article.
Review.
Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer.
Zhiwei Hu.
Sci Rep, 2020 Feb 20; 10(1). PMID: 32071339    Free PMC article.
A Bayesian network meta-analysis of the efficacy of targeted therapies and chemotherapy for treatment of triple-negative breast cancer.
Huihui Chen, Wei Lu, +3 authors, Yiding Chen.
Cancer Med, 2018 Dec 14; 8(1). PMID: 30525293    Free PMC article.
Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer.
Sabrina A Maisel, Derrick Broka, +5 authors, Joyce Schroeder.
J Transl Med, 2019 Jun 20; 17(1). PMID: 31215437    Free PMC article.
Association of CD44 and CD24 phenotype with lymph node metastasis and survival in triple-negative breast cancer.
Weiyan Zou, Yan Yang, +5 authors, Junbin Wang.
Int J Clin Exp Pathol, 2020 Jun 09; 13(5). PMID: 32509072    Free PMC article.
LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target.
Catharina Hagerling, Mark Owyong, +11 authors, Vicki Plaks.
BMC Cancer, 2020 Jun 12; 20(1). PMID: 32522170    Free PMC article.
TUFT1 Promotes Triple Negative Breast Cancer Metastasis, Stemness, and Chemoresistance by Up-Regulating the Rac1/β-Catenin Pathway.
Weiguang Liu, Guanglei Chen, +6 authors, Bo Chen.
Front Oncol, 2019 Jul 25; 9. PMID: 31338333    Free PMC article.
Cowpea Mosaic Virus Immunotherapy Combined with Cyclophosphamide Reduces Breast Cancer Tumor Burden and Inhibits Lung Metastasis.
Hui Cai, Chao Wang, Sourabh Shukla, Nicole F Steinmetz.
Adv Sci (Weinh), 2019 Aug 28; 6(16). PMID: 31453050    Free PMC article.
RILPL2 regulates breast cancer proliferation, metastasis, and chemoresistance via the TUBB3/PTEN pathway.
Guanglei Chen, Lisha Sun, +3 authors, Weiguang Liu.
Am J Cancer Res, 2019 Sep 10; 9(8). PMID: 31497344    Free PMC article.
Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis.
Nandini Verma, Yaron Vinik, +9 authors, Sima Lev.
Sci Adv, 2020 Sep 17; 6(34). PMID: 32937365    Free PMC article.
Class I histone deacetylase inhibitor suppresses vasculogenic mimicry by enhancing the expression of tumor suppressor and anti-angiogenesis genes in aggressive human TNBC cells.
Aparna Maiti, Qianya Qi, +3 authors, Nitai C Hait.
Int J Oncol, 2019 May 07; 55(1). PMID: 31059004    Free PMC article.
The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells.
Víctor Mayoral-Varo, María Pilar Sánchez-Bailón, +5 authors, Jorge Martín-Pérez.
Cancers (Basel), 2021 Feb 04; 13(3). PMID: 33530373    Free PMC article.
Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions.
Fokhrul Hossain, Samarpan Majumder, Justin David, Lucio Miele.
Cancers (Basel), 2021 Aug 08; 13(15). PMID: 34359640    Free PMC article.
Review.
Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164.
Umar Ndagi, Ndumiso N Mhlongo, Mahmoud E Soliman.
Appl Biochem Biotechnol, 2017 Dec 29; 185(3). PMID: 29282631
SHP2 Potentiates the Oncogenic Activity of β-Catenin to Promote Triple-Negative Breast Cancer.
Elisha Martin, Yehenew M Agazie.
Mol Cancer Res, 2021 Aug 15; 19(11). PMID: 34389690    Free PMC article.