scholarly journals Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer

2016 ◽  
Vol 56 (3) ◽  
pp. R99-R114 ◽  
Author(s):  
Katherine A Leehy ◽  
Tarah M Regan Anderson ◽  
Andrea R Daniel ◽  
Carol A Lange ◽  
Julie H Ostrander
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Fate ◽  
Cancer Progression ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Endocrine Resistance ◽  
Steroid Hormone Receptors ◽  
Breast Tumorigenesis ◽  
The Impact

Steroid hormone receptors (SRs) are heavily posttranslationally modified by the reversible addition of a variety of molecular moieties, including phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. These rapid and dynamic modifications may be combinatorial and interact (i.e. may be sequential, complement, or oppose each other), creating a vast array of uniquely modified receptor subspecies that allow for diverse receptor behaviors that enable highly sensitive and context-dependent hormone action. For example, in response to hormone or growth factor membrane-initiated signaling events, posttranslational modifications (PTMs) to SRs alter protein–protein interactions that govern the complex process of promoter or gene-set selection coupled to transcriptional repression or activation. Unique phosphorylation events allow SRs to associate or disassociate with specific cofactors that may include pioneer factors and other tethering partners, which specify the resulting transcriptome and ultimately change cell fate. The impact of PTMs on SR action is particularly profound in the context of breast tumorigenesis, in which frequent alterations in growth factor-initiated signaling pathways occur early and act as drivers of breast cancer progression toward endocrine resistance. In this article, with primary focus on breast cancer relevance, we review the mechanisms by which PTMs, including reversible phosphorylation events, regulate the closely related SRs, glucocorticoid receptor and progesterone receptor, allowing for precise biological responses to ever-changing hormonal stimuli.

Meeting Highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer

2003 ◽  
Vol 21 (17) ◽  
pp. 3357-3365 ◽  
Author(s):  
Aron Goldhirsch ◽  
William C. Wood ◽  
Richard D. Gelber ◽  
Alan S. Coates ◽  
Beat Thürlimann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Ductal Carcinoma ◽  
Steroid Hormone ◽  
Endocrine Resistance ◽  
Steroid Hormone Receptors ◽  
Average Risk ◽  
Primary Therapy ◽  
High Quality ◽  
The Impact

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor–absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer—both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.

The Impact of microRNAs in Breast Cancer Angiogenesis and Progression

MicroRNA ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 101-109 ◽  
Author(s):  
Kontomanolis N. Emmanuel ◽  
Fasoulakis Zacharias ◽  
Papamanolis Valentinos ◽  
Koliantzaki Sofia ◽  
Dimopoulos Georgios ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factors ◽  
Cancer Progression ◽  
Tumor Development ◽  
Breast Cancer Progression ◽  
Breast Tumorigenesis ◽  
Aberrant Expression ◽  
Serum Microrna ◽  
Cancer Types ◽  
The Impact

Objective: The study aims to review the recent data considering the expression profile and the role of microRNAs in breast tumorigenesis, and their impact on -the vital for breast cancer progression- angiogenesis.Methods:PubMed was searched for studies focused on data that associate microRNA with breast cancer, using the terms ''breast”, “mammary gland”, “neoplasia'', “angiogenesis” and ''microRNA'' between 1997-2018.Results:Aberrant expression of several circulating and tissue miRNAs is observed in human breast neoplasms with the deregulation of several miRNAs having a major participation in breast cancer progression. Angiogenesis seems to be directly affected by either overexpression or down regulation of many miRNAs, defining the overall prognostic rates. Many miRNAs differentially expressed in breast cancer that reveal a key role in suppression - progression and metastasis of breast cancer along with the contribution of the EGF, TNF-a and EGF cytokines.ConclusionAngiogenesis has proven to be vital for tumor development and metastasis while microRNAs are proposed to have multiple biological roles, including participation in immunosuppressive, immunomodulatory and recent studies reveal their implication in angiogenesis and its possible use as prognostic factors in cancer Even though larger studies are needed in order to reach safe conclusions, important steps are made that reveal the connection of serum microRNA expression to the angiogenic course of breast cancer, while miRNAs could be potential prognostic factors for the different breast cancer types.

scholarly journals Cross-talk between ER and HER2 in breast carcinoma

2006 ◽  
Vol 14 (3-4) ◽  
pp. 146-150 ◽  
Author(s):  
Natasa Todorovic-Rakovic ◽  
Zora Neskovic-Konstantinovic ◽  
Dragica Nikolic-Vukosavljevic
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Progression ◽  
Cross Talk ◽  
Transcriptional Activation ◽  
Mapk Pathway ◽  
Endocrine Resistance ◽  
Mitogen Activated Protein Kinase ◽  
Her2 Status ◽  
Normal Mammary Gland

In tumors in which estrogen receptor (ER) and growth factor signaling pathways are simultaneously active, there is a bidirectional cross-talk that results in a positive feedback cycle of cell survival and proliferation stimuli. Beside the postulated inverse correlation between ER and HER2 (human epidermal growth factor receptor 2) as a consequence of repressive feedback signaling loop, there are also other mechanisms regarding ER-HER2 interactions. It seems that MAPK (mitogen-activated protein kinase) pathway has a central role in synergistic action between ER and HER2 in normal mammary gland development, as well in the breast cancer. MAPK pathway is hyperstimulated in cells that overexpress HER2 as a consequence of HER2 gene amplification. In ER+ tumors, MAPK phosphorylates and activates either ER itself or ER coregulators, enhancing the transcriptional activation potential of ER. ER and HER2 signaling could interact on multiple levels (genomic or non-genomic) and therefore might induce reduced ER expression or might increase ER function. Based on our own research, dominant effect of postulated cross-talk was not related to HER2-induced reduced expression of ER (no difference in quantitative levels of ER in ER+ tumors regarding their HER2 status and no difference in progression-free time between ER+HER2- and ER+HER2+ patients) as presented. The importance of understanding ER-HER2 cross-talk is not only because of its significance in breast cancer progression, but because it seems to be fundamental factor in endocrine resistance that can improve treatment strategies, especially targeting MAPK pathway. .

scholarly journals 90 YEARS OF PROGESTERONE: Steroid receptors as MAPK signaling sensors in breast cancer: let the fates decide

2020 ◽  
Vol 65 (1) ◽  
pp. T35-T48
Author(s):  
Amy R Dwyer ◽  
Thu H Truong ◽  
Julie H Ostrander ◽  
Carol A Lange
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Cancer Cell ◽  
Glucocorticoid Receptors ◽  
Hormone Receptors ◽  
Mapk Signaling ◽  
Signaling Molecules ◽  
Steroid Hormone Receptors ◽  
Wide Range

Steroid hormone receptors (SRs) are classically defined as ligand-activated transcription factors that function as master regulators of gene programs important for a wide range of processes governing adult physiology, development, and cell or tissue homeostasis. A second function of SRs includes the ability to activate cytoplasmic signaling pathways. Estrogen (ER), androgen (AR), and progesterone (PR) receptors bind directly to membrane-associated signaling molecules including mitogenic protein kinases (i.e. c-SRC and AKT), G-proteins, and ion channels to mediate context-dependent actions via rapid activation of downstream signaling pathways. In addition to making direct contact with diverse signaling molecules, SRs are further fully integrated with signaling pathways by virtue of their N-terminal phosphorylation sites that act as regulatory hot-spots capable of sensing the signaling milieu. In particular, ER, AR, PR, and closely related glucocorticoid receptors (GR) share the property of accepting (i.e. sensing) ligand-independent phosphorylation events by proline-directed kinases in the MAPK and CDK families. These signaling inputs act as a ‘second ligand’ that dramatically impacts cell fate. In the face of drugs that reliably target SR ligand-binding domains to block uncontrolled cancer growth, ligand-independent post-translational modifications guide changes in cell fate that confer increased survival, EMT, migration/invasion, stemness properties, and therapy resistance of non-proliferating SR+ cancer cell subpopulations. The focus of this review is on MAPK pathways in the regulation of SR+ cancer cell fate. MAPK-dependent phosphorylation of PR (Ser294) and GR (Ser134) will primarily be discussed in light of the need to target changes in breast cancer cell fate as part of modernized combination therapies.

scholarly journals Steroid Hormone Receptors: Links With Cell Cycle Machinery and Breast Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Suryendu Saha ◽  
Samya Dey ◽  
Somsubhra Nath
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Progression ◽  
Hormone Receptors ◽  
Cellular Proliferation ◽  
Steroid Hormone ◽  
Breast Cancer Progression ◽  
Steroid Hormone Receptors ◽  
Cycle Regulation

Progression of cells through cell cycle consists of a series of events orchestrated in a regulated fashion. Such processes are influenced by cell cycle regulated expression of various proteins where multiple families of transcription factors take integral parts. Among these, the steroid hormone receptors (SHRs) represent a connection between the external hormone milieu and genes that control cellular proliferation. Therefore, understanding the molecular connection between the transcriptional role of steroid hormone receptors and cell cycle deserves importance in dissecting cellular proliferation in normal as well as malignant conditions. Deregulation of cell cycle promotes malignancies of various origins, including breast cancer. Indeed, SHR members play crucial role in breast cancer progression as well as management. This review focuses on SHR-driven cell cycle regulation and moving forward, attempts to discuss the role of SHR-driven crosstalk between cell cycle anomalies and breast cancer.

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

2018 ◽  
Vol 18 (6) ◽  
pp. 832-836
Author(s):  
Giuseppe Buono ◽  
Francesco Schettini ◽  
Francesco Perri ◽  
Grazia Arpino ◽  
Roberto Bianco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Translational Research ◽  
Cell Biology ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Heterogeneity ◽  
Therapeutic Implications ◽  
The Impact

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors “omics”, including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research. </P><P> It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

scholarly journals CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2872
Author(s):  
Aaron R. Waddell ◽  
Haojie Huang ◽  
Daiqing Liao
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Cell Cycle Progression ◽  
Hormone Receptors ◽  
Steroid Hormone Receptors ◽  
Breast Cancers ◽  
Creb Binding Protein ◽  
Breast And Prostate Cancer

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

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