Abstract
The translational research strategy of targeting estrogen receptor α (ERα) positive breast cancer and then using long term anti-hormone adjuvant therapy (5-10 years) has reduced recurrences and mortality. However, resistance continues to occur and improvements are required to build on the success of tamoxifen and aromatase inhibitors (AIs) established over the past 40 years. Further translational research has described the evolution of acquired resistance of breast cancer cell lines to long term estrogen deprivation that parallels clinical experience over years. Additionally, recent reports have identified mutations in the ERα obtained from the recurrences of AI treated patients. These mutations allow the ERα to activate without ligands and auto stimulate metastatic tumor growth. Furthermore, the new biology of estrogen-induced apoptosis in acquired resistant models in vitro and in vivo has been interrogated and applied to clinical trials. Inflammation and stress are emerging concepts occurring in the process of acquired resistance and estrogen-induced apoptosis with different mechanisms. In this review, we will present progress in the understanding of acquired resistance, focus on stress and inflammatory responses in the development of acquired resistance, and consider approaches to create new treatments to improve the treatment of breast cancer with endocrine resistance.
Highlights
Estrogen receptor α (ERα) is a critical nuclear transcription factor to mediate cell proliferation and metabolism through binding to its ligand estrogen (E2) in breast cancer
Phosphorylation of insulin-like growth factor-1 receptor (IGF-1R) is increased by tamoxifen due to the non-genomic activity of ERα[32]. All of these findings suggest that SERMs consistently inhibit classical ERα transcriptional activity regardless of being SERM sensitive or resistant breast cancer cells
Our findings demonstrate that both Jun NH2-terminus kinase (JNK) and Akt are commonly regulated by IGF-1R in SERM resistant breast cancer cells[57]
Summary
Estrogen receptor α (ERα) is a critical nuclear transcription factor to mediate cell proliferation and metabolism through binding to its ligand estrogen (E2) in breast cancer. We will review how stressful anti-hormone therapy alters the function of ERα, including its interactions with membrane-associated molecules, mutations, and crosstalk with nuclear inflammation-associated transcription factors, thereby leading to the endocrine resistance. Our findings demonstrate that both JNK and Akt are commonly regulated by IGF-1R in SERM resistant breast cancer cells[57] All together, these factors including growth factor receptors, stress-associated kinases, and AP-1 family members are activated after anti-hormone therapy, which contribute to SERM-resistance in ER-positive breast cancer. The inflammatory factor is able to reprogram the motifs on ERα binding sites on chromatin which is closely associated with the endocrine resistance in breast cancer[108,109] These results demonstrate that long term anti-hormone therapy alters the function of ERα and its interaction with inflammation-associated transcription factors that results in the endocrine resistance in breast cancer.
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