The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast

Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to most types of invasive breast cancer (IBC). Although it is estimated only one third of untreated patients with DCIS will progress to IBC, standard of care for treatment is surgery and radiation. This therapeutic approach combined with a lack of reliable biomarker panels to predict DCIS progression is a major clinical problem. DCIS shares the same molecular subtypes as IBC including estrogen receptor (ER) and progesterone receptor (PR) positive luminal subtypes, which encompass the majority (60–70%) of DCIS. Compared to the established roles of ER and PR in luminal IBC, much less is known about the roles and mechanism of action of estrogen (E2) and progesterone (P4) and their cognate receptors in the development and progression of DCIS. This is an underexplored area of research due in part to a paucity of suitable experimental models of ER+/PR + DCIS. This review summarizes information from clinical and observational studies on steroid hormones as breast cancer risk factors and ER and PR as biomarkers in DCIS. Lastly, we discuss emerging experimental models of ER+/PR+ DCIS.

STAT5-Driven Enhancers Tightly Control Temporal Expression of Mammary-Specific Genes

Abstract

The de novo formation of milk-secreting mammary epithelium during pregnancy is regulated by prolactin through activation of the transcription factor STAT5, which stimulates the expression of several hundred mammary-specific genes. In addition to its key role in activating gene expression in mammary tissue, STAT5, which is ubiquitously expressed in most cell types, implements T cell-specific programs controlled by interleukins. However, the mechanisms by which STAT5 controls cell-specific genetic programs activated by distinct cytokines remain relatively unknown. Integration of data from genome-wide surveys of chromatin markers and transcription factor binding at regulatory elements may shed light on the mechanisms that drive cell-specific programs. Here, we have illustrated how STAT5 controls cell-specific gene expression through its concentration and an auto-regulatory enhancer supporting its high levels in mammary tissue. The unique genomic features of STAT5-driven enhancers or super-enhancers that regulate mammary-specific genes and their dynamic remodeling in response to pregnancy hormone levels are described. We have further provided biological evidence supporting the in vivo function of a STAT5-driven super-enhancer with the aid of CRISPR/Cas9 genome editing. Finally, we discuss how the functions of mammary-specific super-enhancers are confined by the zinc finger protein, CTCF, to allow exclusive activation of mammary-specific genes without affecting common neighboring genes. This review comprehensively summarizes the molecular pathways underlying differential control of cell-specific gene sets by STAT5 and provides novel insights into STAT5-dependent mammary physiology.

Beyond DNA: the Role of Epigenetics in the Premalignant Progression of Breast Cancer

Abstract

Ductal Carcinoma in Situ (DCIS) is an early breast cancer lesion that is considered a nonobligate precursor to development of invasive ductal carcinoma (IDC). Although only a small subset of DCIS lesions are predicted to progress into a breast cancer, distinguishing innocuous from minacious DCIS lesions remains a clinical challenge. Thus, patients diagnosed with DCIS will undergo surgery with the potential for radiation and hormone therapy. This has led to a current state of overdiagnosis and overtreatment. Interrogating the transcriptome alone has yet to define clear functional determinants of progression from DCIS to IDC. Epigenetic changes, critical for imprinting and tissue specific development, in the incorrect context can lead to global signaling rewiring driving pathological phenotypes. Epigenetic signaling pathways, and the molecular players that interpret and sustain their signals, are critical to understanding the underlying pathology of breast cancer progression. The types of epigenetic changes, as well as the molecular players, are expanding. In addition to DNA methylation, histone modifications, and chromatin remodeling, we must also consider enhancers as well as the growing field of noncoding RNAs. Herein we will review the epigenetic interactions that have been uncovered in early stage lesions that impact breast cancer progression, and how these players may be utilized as biomarkers to mitigate overdiagnosis and overtreatment.

Dissecting Tissue-Specific Super-Enhancers by Integrating Genome-Wide Analyses and CRISPR/Cas9 Genome Editing

Abstract

Recent advances in genome-wide sequencing technologies have provided researchers with unprecedented opportunities to discover the genomic structures of gene regulatory units in living organisms. In particular, the integration of ChIP-seq, RNA-seq, and DNase-seq techniques has facilitated the mapping of a new class of regulatory elements. These elements, called super-enhancers, can regulate cell-type-specific gene sets and even fine-tune gene expression regulation in response to external stimuli, and have become a hot topic in genome biology. However, there is scant genetic evidence demonstrating their unique biological relevance and the mechanisms underlying these biological functions. In this review, we describe a robust genome-wide strategy for mapping cell-type-specific enhancers or super-enhancers in the mammary genome. In this strategy, genome-wide screening of active enhancer clusters that are co-occupied by mammary-enriched transcription factors, co-factors, and active enhancer marks is used to identify bona fide mammary tissue-specific super-enhancers. The in vivo function of these super-enhancers and their associated regulatory elements may then be investigated in various ways using the advanced CRISPR/Cas9 genome-editing technology. Based on our experience targeting various mammary genomic sites using CRISPR/Cas9 in mice, we comprehensively discuss the molecular consequences of the different targeting methods, such as the number of gRNAs and the dependence on their simultaneous or sequential injections. We also mention the considerations that are essential for obtaining accurate results and shed light on recent progress that has been made in developing modified CRISPR/Cas9 genome-editing techniques. In the future, the coupling of advanced genome-wide sequencing and genome-editing technologies could provide new insights into the complex genetic regulatory networks involved in mammary-gland development.

Magnetic hyperthermia of breast cancer cells and MRI relaxometry with dendrimer-coated iron-oxide nanoparticles

Recently, some studies have focused on dendrimer nanopolymers as a magnetic resonance imaging (MRI) contrast agent or a vehicle for gene and drug delivery. Considering the suitable properties of these material...

Möglichkeiten und Grenzen der Eigenfetttransplantation

Mithilfe der autologen Transplantation von abgesaugtem subkutanem Fettgewebe lassen sich gute Ergebnisse zum Beispiel bei der Brustvergrößerung erzielen. Der folgende Beitrag beschreibt verschiedene Möglichkeiten, wie Patientinnen und Patienten erfolgreich mit der sogenannten BEAULI™-Methode behandelt werden können.

Aus dem Nähkästchen: fünf Tipps und Tricks für Eingriffe an der Haut

FOBI präsentiert breites Spektrum der ästhetischen Medizin

Die 26. Fortbildungswoche für praktische Dermatologie und Venerologie bot ihren Besuchern in München Ende Juli auch eine Vielzahl ästhetischer Fortbildungsthemen an. Einige der Highlights finden Sie im folgenden Kongressbericht.

Sklerosierung statt Operation

Neues Verfahren gegen Cellulite

Pflege bei irritierender Aknetherapie

Symptomorientierte Therapie der Rosazea

Allergan benennt neue Führungskräfte für Deutschland

Was brennt Ihren Patienten unter den Nägeln?

Nägel dienen dem Schutz und der Stabilität der Finger- und Zehenkuppen sowie der taktilen Sensibilität und fungieren an den Fingern als Greifwerkzeuge. Gleichzeitig stellen kranke Nägel eine kosmetische Einschränkung dar. Nagelerkrankungen verdienen daher ausreichende Beachtung und eine intensive Behandlung.

Zusatz zur Lokalanästhesie und Notfallmedikation

Lifestyle und der Einfluss auf die ästhetische Medizin

Jennifer Ceaser ist eine US-amerikanische Journalistin mit Sitz in Berlin. Seit über 15 Jahren veröffentlicht sie regelmäßig in Print- und Online-Publikationen wie New York Magazine, New York Post, The Independent, London Evening Standard, Conde Nast Traveler. Mit dem Experten Dr. Dirk Gröne spricht sie über den Einfluss der modernen Medien auf das Patientenverhalten.

Inhaltsverzeichnis

Auf stürmischer See

Therapie der androgenetischen Alopezie

Alopecia androgenetica der Frau

Zusammenfassung

Aufgrund der Vielgestaltigkeit der Ausfallsmuster und der zahlreichen möglichen Ursachen betrachten viele Ärzte Haarausfall bei Frauen als crux medicorum. Doch das Problem ist beherrschbar. Grundsätzlich ist zu unterscheiden, ob der Haarausfall durch hormonelle oder nicht hormonelle Ursachen bedingt ist und ob im Fall einer androgenetischen Alopezie eine manifeste Hyperandrogenämie oder nur eine erhöhte Sensitivität der Haarfollikel gegenüber Androgenen vorliegt.