Non-canonical Estrogen Signaling in Endocrine Resistance

Breast cancer is one of the leading causes of cancer related deaths in women worldwide. The disease is extremely heterogenous. A large percentage of the breast cancers are dependent on estrogen signaling and hence respond to endocrine therapies which essentially block the estrogen signaling. However, many of these tumors emerge as endocrine resistant tumors. Many mechanisms have been proposed to explain the emergence of endocrine resistance, which include mutations in the estrogen receptors, cross-talk with other signaling pathways, cancer stem cells etc. This review is focused on the role of non-canonical estrogen receptor signaling in endocrine resistance. Most of the therapeutics which are used currently are targeting the major receptor of estrogen namely ER-α. Last two decades has witnessed the discovery of alternate forms of ER-α, as well as other receptors for estrogen such as ERRgamma, GPER-1 as well as ER-β, which are activated not only by estrogen, but also by the therapeutic agents such as tamoxifen that are routinely used in treatment of breast cancer. However, when the alternate receptors are activated, they result in activation of membrane signaling which subsequently activates pathways such as MAPK and GPCR leading to cell-proliferation. This renders the anticipated anti-estrogenic effects of tamoxifen less effective or ineffective. Future research in this area has to focus on the alternate mechanisms and develop a combinatorial strategy, which ...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research

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In conclusion, PLB exerted anti-cancer activity and eliminated stem-like properties by attenuating Wnt/β-catenin signaling and FGF2 expression. These findings suggest that PLB could be a promising agent to treat endocrine resistant breast cancer.Graphical abstract
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
Damu Tang Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core compo...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
In conclusion, e-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment. Introduction Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment (1). In particular, triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR) and HER2 receptors, which is one of the most aggressive types of breast cancers, marked by high rates of relapse, visceral metastases and early death (2, 3). The...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, our WGCNA analysis identified candidate prognostic biomarkers for further basic and clinical researches. Introduction Breast cancer is a frequently diagnosed malignancy and the leading cause of cancer death among females around the world, accounting for 24% of cancer diagnoses and 15% of cancer deaths in females. According to Global Cancer Statistics 2018, there will be nearly 2.1 million new cases diagnosed globally, with ~62 thousand deaths. The incident rates of breast cancer increased in most developing countries during last decades, resulting from a combination of social and economic factors, incl...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSION: Breast cancer cells can develop a pluripotent program with enhanced stemness activity that may together contribute to universal resistance to sex hormonal stimulation or deprivation. Isolation and characterization of patient-derived breast cancer stem cells in large clinical studies is therefore crucial to identify new targets for endocrine therapies, potentially directed towards stemness and pluripotency markers. Such direction may help overcoming endocrine resistance and draw attention to breast cancer stem cells' behaviour under endogenous and exogenous sex hormones throughout a woman's reproductive life. ...
Source: The International Journal of Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Int J Biochem Cell Biol Source Type: research
The detection of recurrent mutations affecting the hormone binding domain (HBD) of estrogen receptor alpha (ER α/ESR1) in endocrine therapy-resistant and metastatic breast cancers has prompted interest in functional characterization of these genetic alterations. Here, we explored the role of HBD-ESR1 mutations in influencing the behaviour of breast cancer stem cells (BCSCs), using various BC cell lines stab ly expressing wild-type or mutant (Y537 N, Y537S, D538G) ERα. Compared to WT-ERα clones, mutant cells showed increased CD44+/CD24- ratio, mRNA levels of stemness genes, Mammosphere Forming Efficiency...
Source: Cancer Letters - Category: Cancer & Oncology Authors: Tags: Original Articles Source Type: research
Introduction: Tumour expression of extrinsic clotting pathway markers are increased in oestrogen receptor (ER) negative, high Ki67, more aggressive breast cancer subtypes. In in vitro and in vivo studies, the extrinsic clotting pathway promotes cancer growth and metastasis.  Cancer stem-like cells (CSCs) are a subpopulation of cancer cells that are resistant to chemotherapy, endocrine therapy and radiotherapy and play a role in recurrence. In vitro, Direct Oral Anticoagulants inhibit breast cancer stem cell activity.
Source: Thrombosis Research - Category: Hematology Authors: Tags: PO-56 Source Type: research
CONCLUSIONS: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine resistant breast cancers, which has both therapeutic and prognostic potential. PMID: 29363524 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Euphemia Y. Leung, Marjan E. Askarian-Amiri, Debina Sarkar, Carole Ferraro-Peyret, Wayne R. Joseph, Graeme J. Finlay, Bruce C. Baguley
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Publication date: Available online 23 April 2017 Source:The Journal of Steroid Biochemistry and Molecular Biology Author(s): Katherine A. Leehy, Thu H. Truong, Laura J. Mauro, Carol A. Lange Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of progesterone during pregnancy signal through PR, inducing expression of the prolactin receptor (PRLR). Cooperation between PR and prolactin (PRL) signaling, v...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research
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