Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy

Abstract

The importance and role of the estrogen receptor (ER) pathway has been well-documented in both breast cancer (BC) development and progression. The treatment of choice in women with metastatic breast cancer (MBC) is classically divided into a variety of endocrine therapies, 3 of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI) and selective estrogen receptor down-regulators (SERD). In a proportion of patients, resistance develops to endocrine therapy due to a sophisticated and at times redundant interference, at the molecular level between the ER and growth factor. The progression to endocrine resistance is considered to be a gradual, step-wise process. Several mechanisms have been proposed but thus far none of them can be defined as the complete explanation behind the phenomenon of endocrine resistance. Although multiple cellular, molecular and immune mechanisms have been and are being extensively studied, their individual roles are often poorly understood. In this review, we summarize current progress in our understanding of ER biology and the molecular mechanisms that predispose and determine endocrine resistance in breast cancer patients.

Keywords: breast cancer; endocrine resistance; estrogen (E2); estrogen receptor; signaling.

Figure 1

Mechanisms involved in endocrine resistance: Several proteins, soluble mediators and transcription factors are assimilated and function cohesively in a complex network, with each entity playing a unique role through the regulation of its own cascade of events as mentioned in each section of this review. In the opinion of the authors, the immune system and the stem cells are at the center of dysregulation observed in the proteins and pathways involved. The soluble mediators, like hormones, cytokines, and chemokines all play a crucial role in BC cells becoming endocrine resistant. IL, interleukin; ROS, reactive oxygen species; mutER, mutations in ERα.

Figure 2

Schematic figure of the structure of ERα and ERβ. The AF1 site is located at the N-terminus A/B domain. The DBD and dimerization site is present within the C domain. The nuclear localization signal is contained in the D domain. The E/F domain contains the AF2 site as well as the ligand binding domain along with a dimerization site. Notable mutations within ERα are depicted for the ERα gene.

Figure 3

(A) Post-translational modifications of the ER. Activation of the growth factor receptor tyrosine kinases leads to phosphorylation of the ER through the RAS-MAPK and PI3K-AKT pathways. Several other pathways, including the CDK2 complex, CDK7/TFIIH complex can also phosphorylate the ER. Sensitivity to E2 is modulated by acetylation of the ER by src (CREB-binding protein). Pictorially represented above are the domains of the ER with phosphorylation/acetylation sites and the protein kinases mediating these modifications. (B) Regulation by E2 at the molecular level: A schematic representation of the pathways and the associated small molecule inhibitors involved in endocrine resistance.