Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies

Abstract

Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients.

Keywords: Breast cancer; Endocrine resistance; Mechanisms of resistance; Therapy.

Figure 1.

Mechanisms of endocrine resistance in ER+ breast cancer. ER+ breast cancer cells may acquire resistance to endocrine therapy by various mechanisms: ER modulation: Regulation of ER during endocrine resistance involves loss of ER, ER phosphorylation by growth factor signaling, ER activating mutations or ER fusions which have constitutive transcriptional activity, leading to enhanced cell growth and migration. Coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators: Increased expression of ER co-activators, such as Steroid Receptor Coactivator 1/3 (SRC-1/3), TFs such as Forkhead Box A1 (FOXA1) or histone modifiers, such as histone deacetylase (HDACs), or reduced levels of ER corepressor, such as Nuclear Receptor Corepressor 1 (NCOR) or the Progesterone Receptor (PR) leads to reprograming of ER transcriptional landscape, promoting the transcription of genes related to cell survival. Regulation of Signaling Pathways: Activation or overexpression of growth factor receptors or their ligands trigger downstream PI3K/AKT/mTOR and RAS/MEK/ERK pathways leading to enhanced cell growth and proliferation. Activation of the stemness inducers, Notch and Wnt signaling also triggers stem cell properties and endocrine resistance by activating the transcriptional program controlled by the intracellular domain of the notch protein (NICD) and β-catenin. Activation of EMT transcription factors (TFs), such as ZEB1, Twist and Slug leads to transcription of mesenchymal and cancer stem cell (CSC) markers that further leads to protection from apoptosis. Modulation of cell cycle progression: Amplification or activation of Cyclin D1/cyclin-dependent kinases 4/6 (CDK4/6) or Cyclin E/CDK2 mediates hyperphosphorylation and inactivation of retinoblastoma (RB) in early and late G1, respectively, leading to increased transcription of S phase genes. Furthermore, increased c-Myc modulates the transcription of G1/S transition regulators. Stress signaling: PDE4D upregulation reduces cAMP levels that protects cells from endoplasmic reticulum (EnR) stress-induced cell death, while overexpression of the heat shock protein, Heat Shock Protein Family B (Small) Member 8 (HSPB8) mediates endocrine resistance via suppressing pro-apoptotic autophagy. Tumor microenvironment, nutrient stress, and metabolic regulation: Enhanced collagen/fibronectin fibers activates integrin signaling, leading to PI3K/AKT activation and cell survival in the presence of endocrine therapy. Secreted soluble factors, cytokines or vesicle-embedded miRNA by cancer-associated fibroblasts (CAFs) or tumor-associated macrophages (TAMs) may reduce ER expression, promote cancer cell survival and stemness, leading to endocrine resistance. Endocrine resistant cells may also exhibit enhanced import of acidic amino acids by upregulation of Solute Carrier Family 1 Member 2 (SLC1A2) or activation of fatty acid receptors, such as Free Fatty Acid Receptor 4 (FFAR4), leading to activation of survival signaling.

Figure 2.

Current and potential future therapeutic options to treat endocrine resistant ER+ breast cancer patients. Current treatment options to treat endocrine resistant ER+ patients include targeting of the cell cycle modulator kinases, cyclin-dependent kinases 4/6 (CDK4/6) by palbociclib, ribociclib and abemaciclib; targeting of mechanistic target of rapamycin (mTOR) kinase by Everolimus; and targeting of P110α subunit of Phosphoinositide 3-kinase (PI3K) by alpelisib. In addition to these strategies, there are several inhibitors that are currently under clinical investigation for the treatment of endocrine resistant ER+ patients such as the AKT Serine/Threonine Kinase (AKT) inhibitor, ipatasertib; the ER partial agonist, TTC-352; the ER proteolysis targeting chimeras (PROTACs), ARV-471; the next-generation selective ER down-regulator (SERD), elacestrant; the epidermal growth factor receptor 1 &2 (EGFR/HER2) dual inhibitor, neratinib; the HER2 targeting antibody-drug conjugate, trastuzumab deruxtecan; and the histone deacetylase (HDAC) inhibitor, entinostat.