Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies

Abstract

Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.

Keywords: CDK4/6 inhibitors; RNAi; SERD; SERM; anti-estrogen therapy; aromatase inhibitors; estrogen receptor-positive breast cancer; resistance; targeted therapies.

Figure 1

Schematic structure and sequence organization of ERα and ERβ. They differ in terms of amino acid numbers. ERα consists of 595 amino acids, while ERβ contains 530 amino acids. ERα and ERβ share identical characteristics. They are formed by different domains. Amino-terminal A/B domains share 18% amino-acid homology between the ERs. C region (97%) consists of DNA-binding domain. D domain (30%) contains a nuclear localization signal. Multifunctional carboxyl-terminal (E) domain, which shows 59% amino-acid identity between the ERs. The carboxyl-terminal F domain shares an 18% amino-acid identity. (DBD: DNA-binding domain; LBD: ligand-binding domain; AF-1: activation domain).

Figure 2

Schematic representation of ERα isoforms including ERα-66, ERα-46, ERα36, and ERα-30. (DBD: DNA-binding domain; LBD: ligand-binding domain; AF-1: activation domain-1; AF-2 activation domain-2).

Figure 3

Illustration of ER signaling pathways. In ligand-dependent signaling, 1: Estrogen binds to intracellular ER and translocates to nucleus for binding to estrogen response elements (EREs) in target gene promoters regulating estrogen-responsive genes, 2: Estrogen binds to intracellular ER and translocates to nucleus for binding to transcription factors (TFs), 3: Estrogen binds to membrane-associated ER and induces signaling molecules, including Src tyrosine kinase, mitogen-activated protein kinase (MAPK), PI3K/AKT, and protein kinase C, regulating transcription of target genes by phosphorylating transcription factors. In ligand-independent signaling, 4: Growth factors bind to growth factor receptors (GFR) to activate intracellular kinases. GFR downstream kinases activate ERs dimerization by phosphorylation and regulate target gene expression in absence of estrogen in both ERE-dependent nuclear signaling or by interacting with other transcription factors.

Figure 4

Resistance mechanisms to anti-estrogen therapies.