New insights into acquired endocrine resistance of breast cancer

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 estrogeninduced 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.

MAGI1, a New Potential Tumor Suppressor Gene in Estrogen Receptor Positive Breast Cancer

“…However, their routine use as adjuvant treatment in BC is still inconsistent and not yet recommended [72][73][74][75][76][77][78][79]. Of interest, mounting evidence indicate that inflammation may promote acquired endocrine resistance and more aggressive progression or ER + BC [80][81][82][83]. Whether MAGI1 is part of this mechanism, and whether this protein is possibly regulated by other tumor-promoting mediators of inflammation (e.g., TNF, IL6) is an attractive hypothesis that deserves further investigations.…”

Mechanisms of allosteric and mixed mode aromatase inhibitors

“…We resolved the stereochemistry of compound AR13 using 1D and 2D NMR, which supported a trans configuration at the cyclopropane moiety. In brief, very weak through-space coupling and a 3 J value of 3.4 supported protons with an uneclipsed dihedral (Figure S1, S2).…”

“…lβ-hydrogen abstraction and electron transfer furnish the A-ring aromatization and loss of a formate molecule to complete a single turnover 2 . As such, aromatase inhibition is a common strategy to treat patients with hormone-dependent breast cancer 3 . Third-generation aromatase inhibitors (AIs) are used as primary therapeutics and long-term adjuvants in postmenopausal women with breast cancer.…”

Alzheimer’s Disease, and Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Outputs and Impact of Funded Research

“…For example, although hormone therapies (e.g., tamoxifen, inhibitors of aromatase enzymes involved in estrogens synthesis) and Herceptin (trastuzumab) have improved clinical outcome of poor prognosis for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-positive cancers, respectively, many patients develop progressive disease [92][93][94]. This suggests that, despite drugs successfully passing preclinical and clinical phases, reaching marketing approval, they may still prove ineffective in the long term.…”