• Targeted therapies for breast cancer
  • Tara Nakhaie,1,*
    1. Department of Laboratory Science , TMS.C., Islamic Azad University, Tehran, Iran


  • Introduction: Breast cancer remains a formidable contender in the global health challenge landscape, with its complex pathogenesis and diverse clinical manifestations, which pose significant barriers to effective treatment and prevention. [1]
  • Methods: Factors that cause breast cancer: The main risk factors include a combination of genetic predisposition, hormonal factors, reproductive history, and lifestyle choices [1]. Genetic factors: Genetic predisposition is the first and most significant component. Hereditary susceptibility to breast cancer is based on an identified germline mutation in one allele of a susceptibility gene with moderate to high penetrance (such as BRCA1/2, CHEK2, PALB2, and TP53). Inactivation of the second allele of tumor suppressor genes would be an early event in this oncogenic pathway. Protein-truncating variants in five genes (ATM, BRCA1/2, CHEK2, and PALB2) have been associated with breast cancer risk.[1]
  • Results: Genetic Investigations: Pathway Interference in Breast Cancer: Increasing evidence suggests that activation of the prolactin (PRL) receptor (PRLR) and the erythroblastic leukemia viral oncogene homolog receptor (ErbBR) drives cancer in the mammary glands, supports breast tumor growth, and induces resistance to chemotherapy. Amplification of epidermal growth factor receptor (EGFR), HER2, and also PRLR in breast cancers accelerates tumor growth by activating their downstream signaling pathways. PRL secretion from breast cells leads to activation of downstream PRLR signaling. This includes activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) and mitogen-activated protein kinase (MAPK) pathways, which are involved in breast tumorigenesis.[2] Role of p53: The tumor suppressor p53 is a master transcription factor involved in the regulation of several cellular functions. In cancer, p53 reduces cell proliferation in response to various stimuli, including DNA damage, nutrient deprivation, hypoxia, and hyperproliferative signals, thereby preventing tumor formation. Under normal physiological conditions, p53 levels are tightly regulated by MDM2, an E3 ligase that degrades p53 via the ubiquitin-proteasome-dependent pathway. p53 can also induce MDM2 expression by binding to its promoter. This creates a negative feedback loop to promote p53 degradation to maintain low cellular p53. In the presence of cellular stresses, p53 undergoes a series of post-translational modifications, such as phosphorylation, which stabilizes p53 by disrupting its interaction with MDM2, Binding to specific DNA sequences, transactivation in which p53 activates or represses its target genes that are involved in cell cycle control, DNA repair, and induction of senescence and apoptosis.[3] Role of the HER2 oncogene: The HER2 oncogene is a well-defined BC biomarker for targeted therapies. Since anti-HER2 therapy enhances the therapeutic efficacy of chemotherapy, a class of antibody-drug conjugates (ADCs) have been developed to maximize the cytotoxic effect of anti-HER2 therapy and chemotherapy through selective endocytosis in HER2+ tumor cells.[4] Role of PI3K/AKT/MTOR: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that can be divided into three classes (I, II, and III) in mammals. In particular, class I PI3K is a well-studied subgroup and has been implicated in the occurrence and development of cancer. Class I PI3K, protein kinase B (PKB/AKT), and the mechanistic target of rapamycin (mTOR) pathway (PAM pathway) often show abnormal activation in human cancer and play critical roles in cell survival, proliferation, motility, and metabolism.[5]
  • Conclusion: Targeted drug therapy: Surgery followed by radiotherapy and chemotherapy is the standard treatment protocol for managing breast cancer. The goal of chemotherapy after surgery or radiotherapy is to reduce the chance of the cancer coming back. Targeted drug therapy targets target proteins on breast cancer cells that support their growth, spread, and ability to multiply. The most effective treatments for breast cancer are those that specifically target the ER and HER2 receptors. Growing evidence has suggested some promising new treatments for various types of breast cancer, including TNBC and HER2+ carcinomas. The course of breast cancer is largely influenced by estrogen and the estrogen receptor (ER).[2] The first drug approved for the treatment of advanced ER+ breast cancer was tamoxifen, which reduces tumor recurrence by approximately 40 to 50 percent. SERMs have actually been used to limit cancer growth in estrogen-dependent forms of breast cancer. Inhibitors of any of the targets, such as PARP, HER2, PI3K, AKT, mammalian target of rapamycin (mTOR), fibroblast growth factor (FGF) receptors (FGFRs), and vascular endothelial growth factor (VEGF), can be used as therapeutic approaches to halt breast cancer progression due to their roles in various carcinogenesis pathways, including cell cycle, angiogenesis, metastasis, etc. [2] These inhibitors have already shown clinical potential. An MTOR inhibitor, zortres (42-O-(2-hydroxyethyl) rapamycin), has been approved for aromatase antagonist-resistant ER+ advanced or metastatic breast cancer. [2] Aromatase inhibitors, endocrine therapy, selective ER modulators (SERMs), and selective estrogen receptor modulators (SERDs) are all recognized forms of personalized therapy for HER2+ breast cancer. The course of breast cancer is largely influenced by estrogen and the estrogen receptor (ER).[2] The first drug approved for the treatment of advanced ER+ breast cancer was tamoxifen, which reduces tumor recurrence by approximately 40 to 50 percent. SERMs have actually been used to limit cancer growth in estrogen-dependent forms of breast cancer. Inhibitors of any of the targets, such as PARP, HER2, PI3K, AKT, mammalian target of rapamycin (mTOR), fibroblast growth factor (FGF) receptors (FGFRs), and vascular endothelial growth factor (VEGF), can be used as therapeutic approaches to halt breast cancer progression due to their roles in various carcinogenesis pathways, including cell cycle, angiogenesis, metastasis, etc. [2] These inhibitors have already shown clinical potential. One mTOR inhibitor, zortres (42-O-(2-hydroxyethyl) rapamycin), has been approved for aromatase antagonist-resistant ER+ advanced or metastatic breast cancer. [2
  • Keywords: Breast Cancer , Targeted Therapy , Genetic Investigations