Emerging therapeutic strategies and opportunities in targeting protein pathways for breast cancer treatment: a critical review

Emerging therapeutic strategies and opportunities in targeting protein pathways for breast cancer treatment: a critical review Panneerselvam Theivendren http://orcid.org/0000-0002-8197-4688 Parasuraman Pavadai http://orcid.org/0000-0002-0779-4750 Selvaraj Kunjiappan http://orcid.org/0000-0002-6741-5118 Kaveena Ravi Natarajan Kiruthiga Kumarappan Chidamabaram Shanmugarathinam Alagarsamy Nagireddy Bhuvan Reddy Abstract

Understanding breast cancer at a molecular level is essential for developing effective treatments due to its significant impact on women’s mortality rates globally. Targeted medicines focus on specific proteins crucial to breast cancer progression, offering a promising treatment avenue. These proteins, often overexpressed or mutated in cancer cells, are vital for cell proliferation, division, and survival. Targeted drugs aim to inhibit these proteins, halting disease progression and sparing non-cancerous cells, which reduces side effects and improves patient quality of life. Key proteins in breast cancer treatment include HER2 (human epidermal growth factor receptor 2), ER (estrogen receptor), and PR (progesterone receptor). Drugs like Trastuzumab target HER2 to impede tumor growth in HER2-positive cancers, while hormone therapies targeting ER and PR improve outcomes for hormone receptor-positive cancers. Examining proteins such as EGFR, HER2/Neu, and ER reveals their roles in cancer pathways, with pathways like PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) and MAPK (mitogen-activated protein kinase) being crucial targets for therapies, potentially revolutionizing breast cancer treatment.
05 19 2025 06 09 2025 232001 10.1088/crossmark-policy iopscience.iop.org Emerging therapeutic strategies and opportunities in targeting protein pathways for breast cancer treatment: a critical review Nanotechnology paper © 2025 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved. 2024-11-08 2025-05-09 2025-05-19 https://iopscience.iop.org/page/copyright https://iopscience.iop.org/info/page/text-and-data-mining 10.1088/1361-6528/add6ae https://iopscience.iop.org/article/10.1088/1361-6528/add6ae https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf https://iopscience.iop.org/article/10.1088/1361-6528/add6ae https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf https://iopscience.iop.org/article/10.1088/1361-6528/add6ae https://iopscience.iop.org/article/10.1088/1361-6528/add6ae/pdf Andrés Aguayo 2018 The role of msi2 in adult and embryonic hematopoiesis Int. Immunopharmacol. Arif 10.1016/j.intimp.2022.109581 114 2023 The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer Mol. Aspect Med. Bertram 10.1016/S0098-2997(00)00007-8 21 167 2000 The molecular biology of cancer Br. J. Haematol. Blachly 10.1111/bjh.13065 167 19 2014 Targeting PI 3‐kinase (PI 3 K), AKT and m TOR axis in lymphoma Biochim. Biophys. Acta Boice 10.1016/j.bbamcr.2020.118688 1867 2020 Targeting apoptotic caspases in cancer Brantley-Sieders 2022 J. Cell Biol. Brugarolas 10.1083/jcb.141.2.503 141 503 1998 p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells Mini Rev. Med. Chem. Buumba 10.2174/1389557521666210126125200 21 2103 2021 A critical review on recent development of techniques and drug targets in the management of breast cancer Cancers Cheng 10.3390/cancers15215209 15 5209 2023 Harnessing ferroptosis to overcome drug resistance in colorectal cancer: promising therapeutic approaches Cell Cycle Dedes 10.4161/cc.10.8.15273 10 1192 2011 Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations Cells Delou 10.3390/cells8091013 8 1013 2019 Highlights in resistance mechanism pathways for combination therapy Mol. Biol. Cell Dent 10.1091/mbc.10.8.2493 10 2493 1999 Radiation-induced release of transforming growth factor α activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death Life Sci. Dinakar 10.1016/j.lfs.2022.120996 309 2022 Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors Int. J. Mol. Sci. Ding 10.3390/ijms21061960 21 1960 2020 The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer Comput. Struct. Biotechnol. J. Dlamini 10.1016/j.csbj.2020.08.019 18 2300 2020 Artificial intelligence (AI) and big data in cancer and precision oncology J. Chemother. Dou 10.1080/1120009X.2023.2278014 36 370 2023 Recent advances in caspase-3, breast cancer, and traditional Chinese medicine: a review Breast Cancer Res. Eccles 10.1186/bcr3493 15 1 2013 Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer Cell. Signal. El-Tanani 10.1016/j.cellsig.2022.110492 101 2023 Cellular and molecular basis of therapeutic approaches to breast cancer Breast Cancer Res. Farmer 10.1186/bcr1122 7 1 2005 Identification of molecular apocrine breast tumours by microarray analysis Rom. J. Morphol. Embryol. Fernandez-Flores 53 879 2012 Immunohistochemical and morphologic evaluation of primary cutaneous apocrine carcinomas and cutaneous metastases from ductal breast carcinoma Oncogene Ferreira 10.1038/onc.2011.576 31 3999 2012 Metabolic reprogramming of the tumor Sci. Am. Folkman 10.1038/scientificamerican0576-58 234 58 1976 The vascularization of tumors Nat. Rev. Drug Discov. Furuhashi 10.1038/nrd2589 7 489 2008 Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets Int. J. Occup. Environ. Health Gray 10.1179/oeh.2009.15.1.43 15 43 2009 State of the evidence: the connection between breast cancer and the environment Soc. Sci. Med. Hanson 10.1016/j.socscimed.2018.11.009 220 150 2019 Cancer risk in socially marginalised women: an exploratory study Hinterding 2022 Jain 2013 Cancer Epidemiol. Biomarkers Prev. Jemal 10.1158/1055-9965.EPI-10-0437 19 1893 2010 Global patterns of cancer incidence and mortality rates and trends Jiang vol 35 S244 2015 J. Cancer Metastat. Treat. Jusino 10.20517/2394-4722.2018.24 4 43 2018 Centrosome aberrations and chromosome instability contribute to tumorigenesis and intra-tumor heterogeneity Cancers Kawiak 10.3390/cancers14020279 14 279 2022 Regulation of Bcl-2 family proteins in estrogen receptor-positive breast cancer and their implications in endocrine therapy Kerr 2021 Nat. Rev. Cancer Lim 10.1038/s41568-018-0010-y 18 485 2018 Inflammatory breast cancer biology: the tumour microenvironment is key Mol Cancer Liu 10.1186/s12943-017-0742-4 16 1 2017 Factors involved in cancer metastasis: a better understanding to “seed and soil” hypothesis BBA Clin. Lukong 10.1016/j.bbacli.2017.01.001 7 64 2017 Understanding breast cancer–The long and winding road Cancers Li 10.3390/cancers12102767 12 2767 2020 Non-invasive biomarkers for early detection of breast cancer J. Proteomics Yao 10.1016/j.jprot.2020.103991 230 2021 Identification of blood protein biomarkers for breast cancer staging by integrative transcriptome and proteome analyses Curr. Drug Targets Marchio 10.2174/1389450116666150203121218 18 4 2017 Predictive diagnostic pathology in the target therapy era in breast cancer Am. Soc. Clin. Oncol. Educ. Book Martin 10.1200/EDBK_159167 36 e64 2016 Emerging therapeutic options for HER2-positive breast cancer Annu. Rev. Physiol. Matsumoto 10.1146/annurev-physiol-030212-183656 75 201 2013 The androgen receptor in health and disease Crit. Rev. Oncog. Mc Cormack 10.1615/CritRevOncog.v13.i4.20 13 283 2007 Role of the progesterone receptor (PR) and the PR isoforms in breast cancer Milella 10.1007/978-1-4419-0507-9_2 37 2010 Signal transduction pathways as therapeutic targets in cancer therapy Proc. Natl Acad. Sci. Mira 10.1073/pnas.97.1.185 97 185 2000 Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway Genes Dis. Mohanty 10.1016/j.gendis.2020.12.005 9 648 2022 Role of hormone receptors and HER2 as prospective molecular markers for breast cancer: an update Breast Cancer: Target Ther. Nahta 10.2147/BCTT.S24976 4 53 2012 New developments in the treatment of HER2-positive breast cancer Breast Nielsen 10.1016/j.breast.2012.09.008 22 1 2013 Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors Breast Cancer Nounou 10.4137/BCBCR.S29420 9 BCBCR 2015 Breast cancer: conventional diagnosis and treatment modalities and recent patents and technologies Mol. Cell. Biochem. Ola 10.1007/s11010-010-0709-x 351 41 2011 Role of Bcl-2 family proteins and caspases in the regulation of apoptosis Onody 2006 Curr. Mol. Pharmacol. Kourea H 10.2174/187446720701150105170830 7 4 2014 Targeted pathways in breast cancer: molecular and protein markers guiding therapeutic decisions Pharmacol. Ther. Patel 10.1016/j.pharmthera.2017.12.012 186 1 2018 Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment Front. Oncol. Peng 10.3389/fonc.2022.819128 12 2022 PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? Pharmacol. Ther. Pitts 10.1016/j.pharmthera.2013.12.010 142 258 2014 Targeting nuclear kinases in cancer: development of cell cycle kinase inhibitors JAMA Plevritis 10.1001/jama.2017.19130 319 154 2018 Association of screening and treatment with breast cancer mortality by molecular subtype in US women, 2000–2012 Pradubyat 2020 Biochem. Pharmacol. Renoir 10.1016/j.bcp.2012.10.018 85 449 2013 Estrogen receptor signaling as a target for novel breast cancer therapeutics Cancer Treat. Rev. Saini 10.1016/j.ctrv.2013.03.009 39 935 2013 Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer Cancer Chemother. Pharmacol. Schiff 10.1007/s00280-005-0108-2 56 10 2005 Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators Schneider 2023 Breast Cancer Res. Selli 10.1186/s13058-016-0779-0 18 1 2016 Accurate prediction of response to endocrine therapy in breast cancer patients: current and future biomarkers Cancers Sellitto 10.3390/cancers12061477 12 1477 2020 Insights into the role of estrogen receptor β in triple-negative breast cancer Cancer Discov. Sherr 10.1158/2159-8290.CD-15-0894 6 353 2016 Targeting CDK4 and CDK6: from discovery to therapy Adv. Biomed. Res. Shruthi 10.4103/2277-9175.180636 5 67 2016 Proteomics: a new perspective for cancer PLoS One Singh 10.1371/journal.pone.0109487 9 2014 Highly adaptable triple-negative breast cancer cells as a functional model for testing anticancer agents Matrix Biol. Skandalis 10.1016/j.matbio.2013.09.002 35 182 2014 Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans Antibodies Song 10.3390/antib12040072 12 72 2023 Trends in the development of antibody-drug conjugates for cancer therapy Aging Steelman 10.18632/aging.100296 3 192 2011 Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging Nat. Rev. Drug Discov. Swain 10.1038/s41573-022-00579-0 22 101 2023 Targeting HER2-positive breast cancer: advances and future directions Nat. Rev. Cancer Thomas 10.1038/nrc3093 11 597 2011 The different roles of ER subtypes in cancer biology and therapy Cancers To 10.3390/cancers14020429 14 429 2022 STAT3 signaling in breast cancer: multicellular actions and therapeutic potential Am. Family Phys. Trayes 104 171 2021 Breast cancer treatment Cell. Mol. Immunol. Varadé 10.1038/s41423-020-00530-6 18 805 2021 Human immunology and immunotherapy: main achievements and challenges Endocr. Relat. Cancer Weigel 10.1677/ERC-10-0136 17 R245 2010 Current and emerging biomarkers in breast cancer: prognosis and prediction Fam. Syst. Health Werner-Lin 10.1037/a0028434 30 166 2012 “My funky genetics”: BRCA1/2 mutation carriers’ understanding of genetic inheritance and reproductive merger in the context of new reprogenetic technologies Adv. Cancer Res. Williams 10.1016/bs.acr.2015.04.008 127 253 2015 Perspectives on epidermal growth factor receptor regulation in triple-negative breast cancer: ligand-mediated mechanisms of receptor regulation and potential for clinical targeting Yance 2005 Adv. Mater. Yang 10.1002/adma.201802896 31 2019 Exosome biochemistry and advanced nanotechnology for next‐generation theranostic platforms Cells Yip 10.3390/cells10030659 10 659 2021 Signaling pathways in cancer: therapeutic targets, combinatorial treatments, and new developments