The Endocrine Treatment Landscape for Patients with HR+ HER2- Early-stage Breast Cancer in Germany Before the Introduction of CDK4/6 Inhibitor Therapy - A Real-World Analysis.

Introduction: While premenopausal patients with HR+ HER2- early breast cancer are treated with tamoxifen +/- ovarian suppression with a GnRH analog or an aromatase inhibitor (AI) + GnRH, the majority of postmenopausal women receive an AI due to its higher efficacy compared to tamoxifen. As the introduction of CDK4/6 inhibitors into the treatment of early-stage breast cancer with a higher risk of recurrence will probably result in a shift in the endocrine treatment landscape, the question is what treatment did potential candidates for CDK4/6 inhibitors in Germany receive before CDK4/6 inhibitors were available.

Patients And Methods: As part of a retrospective multicenter analysis, anonymized data were collected of patients with HR+ HER2- early-stage breast cancer who received endocrine therapy in the period between 10/2021 and 03/2022.

The SAFEGUARD1 suppresses singlet oxygen-induced stress responses by protecting grana margins.

Singlet oxygen (O), the major reactive oxygen species (ROS) produced in chloroplasts, has been demonstrated recently to be a highly versatile signal that induces various stress responses. In the () mutant, its release causes seedling lethality and inhibits mature plant growth. However, these drastic phenotypes are suppressed when EXECUTER1 (EX1) is absent in the double mutant.

Dose-dependent effects of 1O2 in chloroplasts are determined by its timing and localization of production.

In plants, highly reactive singlet oxygen (1O2) is known to inhibit photosynthesis and to damage the cell as a cytotoxin. However, more recent studies have also proposed 1O2 as a signal. In plants under stress, not only 1O2 but also other reactive oxygen species (ROS) are generated simultaneously, thus making it difficult to link a particular response to the release of 1O2 and establish a signaling role for this ROS.

Singlet oxygen- and EXECUTER1-mediated signaling is initiated in grana margins and depends on the protease FtsH2.

Formation of singlet oxygen ((1)O2) has been implicated with damaging photosystem II (PSII) that needs to undergo continuous repair to maintain photosynthetic electron transport. In addition to its damaging effect, (1)O2 has also been shown to act as a signal that triggers stress acclimation and an enhanced stress resistance. A signaling role of (1)O2 was first documented in the fluorescent (flu) mutant of Arabidopsis It strictly depends on the chloroplast protein EXECUTER1 (EX1) and happens under nonphotoinhibitory light conditions.

Blocking the QB-binding site of photosystem II by tenuazonic acid, a non-host-specific toxin of Alternaria alternata, activates singlet oxygen-mediated and EXECUTER-dependent signalling in Arabidopsis.

Necrotrophic fungal pathogens produce toxic compounds that induce cell death in infected plants. Often, the primary targets of these toxins and the way a plant responds to them are not known. In the present work, the effect of tenuazonic acid (TeA), a non-host-specific toxin of Alternaria alternata, on Arabidopsis thaliana has been analysed.

Singlet oxygen-mediated and EXECUTER-dependent signalling and acclimation of Arabidopsis thaliana exposed to light stress.

Plants respond to environmental changes by acclimation that activates defence mechanisms and enhances the plant's resistance against a subsequent more severe stress. Chloroplasts play an important role as a sensor of environmental stress factors that interfere with the photosynthetic electron transport and enhance the production of reactive oxygen species (ROS). One of these ROS, singlet oxygen ((1)O2), activates a signalling pathway within chloroplasts that depends on the two plastid-localized proteins EXECUTER 1 and 2.

A novel proteinase, SNOWY COTYLEDON4, is required for photosynthetic acclimation to higher light intensities in Arabidopsis.

Excess light can have a negative impact on photosynthesis; thus, plants have evolved many different ways to adapt to different light conditions to both optimize energy use and avoid damage caused by excess light. Analysis of the Arabidopsis (Arabidopsis thaliana) mutant snowy cotyledon4 (sco4) revealed a mutation in a chloroplast-targeted protein that shares limited homology with CaaX-type endopeptidases. The SCO4 protein possesses an important function in photosynthesis and development, with point mutations rendering the seedlings and adult plants susceptible to photooxidative stress.

Singlet oxygen-mediated signaling in plants: moving from flu to wild type reveals an increasing complexity.

Singlet oxygen ((1)O2)-mediated signaling has been established in the conditional fluorescent (flu) mutant of Arabidopsis. In the dark, the flu mutant accumulates free protochlorophyllide (Pchlide), a photosensitizer that in the light generates (1)O2. The release of (1)O2 leads to growth inhibition of mature plants and bleaching of seedlings.

1O2-mediated and EXECUTER-dependent retrograde plastid-to-nucleus signaling in norflurazon-treated seedlings of Arabidopsis thaliana.

Chloroplast development depends on the synthesis and import of a large number of nuclear-encoded proteins. The synthesis of some of these proteins is affected by the functional state of the plastid via a process known as retrograde signaling. Retrograde plastid-to-nucleus signaling has been often characterized in seedlings of Arabidopsis thaliana exposed to norflurazon (NF), an inhibitor of carotenoid biosynthesis.

Integration of stress-related and reactive oxygen species-mediated signals by Topoisomerase VI in Arabidopsis thaliana.

Environmental stress often leads to an increased production of reactive oxygen species that are involved in plastid-to-nucleus retrograde signaling. Soon after the release of singlet oxygen ((1)O(2)) in chloroplasts of the flu mutant of Arabidopsis, reprogramming of nuclear gene expression reveals a rapid transfer of signals from the plastid to the nucleus. We have identified extraplastidic signaling constituents involved in (1)O(2)-initiated plastid-to-nucleus signaling and nuclear gene activation after mutagenizing a flu line expressing the luciferase reporter gene under the control of the promoter of a (1)O(2)-responsive AAA-ATPase gene (At3g28580) and isolating second-site mutations that lead to a constitutive up-regulation of the reporter gene or abrogate its (1)O(2)-dependent up-regulation.

Arabidopsis light-dependent NADPH: protochlorophyllide oxidoreductase A (PORA) is essential for normal plant growth and development: an addendum.

Recently the porA-1 null mutant of Arabidopsis thaliana has been identified, which contains an insertion of the Dissociation (Ds) element in the PORA gene (Paddock et al. in Plant Mol Biol 78:447-460, 2012). Light-grown porA-1 seedlings suffer from a drastically reduced chlorophyll content and a developmental arrest beyond the cotyledon stage, suggesting that PORA is not only transiently involved in initiating chlorophyll synthesis during illumination of etiolated seedlings but is also essential for normal growth and plant development.

Chloroplasts of Arabidopsis are the source and a primary target of a plant-specific programmed cell death signaling pathway.

Enhanced levels of singlet oxygen ((1)O(2)) in chloroplasts trigger programmed cell death. The impact of (1)O(2) production in chloroplasts was monitored first in the conditional fluorescent (flu) mutant of Arabidopsis thaliana that accumulates (1)O(2) upon a dark/light shift. The onset of (1)O(2) production is rapidly followed by a loss of chloroplast integrity that precedes the rupture of the central vacuole and the final collapse of the cell.

Arabidopsis light-dependent protochlorophyllide oxidoreductase A (PORA) is essential for normal plant growth and development.

During skotomorphogenesis in angiosperms, NADPH:protochlorophyllide oxidoreductase (POR) forms an aggregate of photolabile NADPH-POR-protochlorophyllide (Pchlide) ternary complexes localized to the prolamellar bodies within etioplasts. During photomorphogenesis, POR catalyzes the light-dependent reduction of Pchlide a to chlorophyllide (Chlide) a, which is subsequently converted to chlorophyll (Chl). In Arabidopsis there are three structurally related POR genes, denoted PORA, PORB and PORC.

FLU, a negative feedback regulator of tetrapyrrole biosynthesis, is physically linked to the final steps of the Mg(++)-branch of this pathway.

Regulation of tetrapyrrole biosynthesis in higher plants has been attributed to negative feedback control. Two effectors of feedback inhibition have been identified, heme and the FLU protein. Inhibition by heme implicates the Fe-branch via regulation of the initial step of tetrapyrrole synthesis.

The SCO2 protein disulphide isomerase is required for thylakoid biogenesis and interacts with LHCB1 chlorophyll a/b binding proteins which affects chlorophyll biosynthesis in Arabidopsis seedlings.

The process of chloroplast biogenesis requires a multitude of pathways and processes to establish chloroplast function. In cotyledons of seedlings, chloroplasts develop either directly from proplastids (also named eoplasts) or, if germinated in the dark, via etioplasts, whereas in leaves chloroplasts derive from proplastids in the apical meristem and are then multiplied by division. The snowy cotyledon 2, sco2, mutations specifically disrupt chloroplast biogenesis in cotyledons.

The chloroplast division mutant caa33 of Arabidopsis thaliana reveals the crucial impact of chloroplast homeostasis on stress acclimation and retrograde plastid-to-nucleus signaling.

Retrograde plastid-to-nucleus signaling tightly controls and coordinates the nuclear and plastid gene expression that is required for plastid biogenesis and chloroplast activity. As chloroplasts act as sensors of environmental changes, plastid-derived signaling also modulates stress responses of plants by transferring stress-related signals and altering nuclear gene expression. Various mutant screens have been undertaken to identify constituents of plastid signaling pathways.

'happy on norflurazon' (hon) mutations implicate perturbance of plastid homeostasis with activating stress acclimatization and changing nuclear gene expression in norflurazon-treated seedlings.

Various mutant screens have been undertaken to identify constituents involved in the transmission of signals from the plastid to the nucleus. Many of these screens have been performed using carotenoid-deficient plants grown in the presence of norflurazon (NF), an inhibitor of phytoene desaturase. NF-treated plants are bleached and suppress the expression of nuclear genes encoding chloroplast proteins.

The cytoskeleton and the peroxisomal-targeted snowy cotyledon3 protein are required for chloroplast development in Arabidopsis.

Here, we describe the snowy cotyledon3 (sco3-1) mutation, which impairs chloroplast and etioplast development in Arabidopsis thaliana seedlings. SCO3 is a member of a largely uncharacterized protein family unique to the plant kingdom. The sco3-1 mutation alters chloroplast morphology and development, reduces chlorophyll accumulation, impairs thylakoid formation and photosynthesis in seedlings, and results in photoinhibition under extreme CO(2) concentrations in mature leaves.

A mutation in the Arabidopsis mTERF-related plastid protein SOLDAT10 activates retrograde signaling and suppresses (1)O(2)-induced cell death.

The conditional flu mutant of Arabidopsis thaliana generates singlet oxygen ((1)O(2)) in plastids during a dark-to-light shift. Seedlings of flu bleach and die, whereas mature plants stop growing and develop macroscopic necrotic lesions. Several suppressor mutants, dubbed singlet oxygen-linked death activator (soldat), were identified that abrogate (1)O(2)-mediated cell death of flu seedlings.

Modulation of O-mediated retrograde signaling by the PLEIOTROPIC RESPONSE LOCUS 1 (PRL1) protein, a central integrator of stress and energy signaling.

Shortly after the release of singlet oxygen ((1)O(2)) in chloroplasts, changes in nuclear gene expression occur in the conditional flu mutant of Arabidopsis that reveal a rapid transfer of signals from the plastid to the nucleus. Extensive genetic screens aimed at identifying constituents involved in (1)O(2)-mediated plastid-to-nucleus signaling have failed to identify extraplastidic signaling components. This finding suggests that (1)O(2)-mediated signals are not translocated to the nucleus via a single linear pathway, but rather through a signaling network that is difficult to block by single mutations.

(1)O2-mediated retrograde signaling during late embryogenesis predetermines plastid differentiation in seedlings by recruiting abscisic acid.

Plastid development in seedlings of Arabidopsis thaliana is affected by the transfer of (1)O(2)-mediated retrograde signals from the plastid to the nucleus and changes in nuclear gene expression during late embryogenesis. The potential impact of these mechanisms on plastid differentiation is maintained throughout seed dormancy and becomes effective only after seed germination. Inactivation of the 2 nuclear-encoded plastid proteins EXECUTER1 and EXECUTER2 blocks (1)O(2)-mediated retrograde signaling before the onset of dormancy and impairs normal plastid formation in germinating seeds.

Arabidopsis mutants reveal multiple singlet oxygen signaling pathways involved in stress response and development.

Shortly after the release of singlet oxygen ((1)O(2)) in chloroplasts drastic changes in nuclear gene expression occur in the conditional flu mutant of Arabidopsis that reveal a rapid transfer of signals from the plastid to the nucleus. Factors involved in this retrograde signaling were identified by mutagenizing a transgenic flu line expressing a (1)O(2)-responsive reporter gene. The reporter gene consisted of the luciferase open reading frame and the promoter of an AAA-ATPase gene (At3g28580) that was selectively activated by (1)O(2) but not by superoxide or hydrogen peroxide.

Characterization of soldat8, a suppressor of singlet oxygen-induced cell death in Arabidopsis seedlings.

The flu mutant of Arabidopsis thaliana overaccumulates in the dark the immediate precursor of chlorophyllide, protochlorophyllide (Pchlide), a potent photosensitizer, that upon illumination generates singlet oxygen ((1)O2). Once (1)O2 has been released in plastids of the flu mutant, mature plants stop growing, while seedlings die. Several suppressor mutations, dubbed singlet oxygen-linked death activator (soldat), were identified that specifically abrogate (1)O2-mediated stress responses in young flu seedlings without grossly affecting (1)O2-mediated stress responses of mature flu plants.

No single way to understand singlet oxygen signalling in plants.

When plant cells are under environmental stress, several chemically distinct reactive oxygen species (ROS) are generated simultaneously in various intracellular compartments and these can cause oxidative damage or act as signals. The conditional flu mutant of Arabidopsis, which generates singlet oxygen in plastids during a dark-to-light transition, has allowed the biological activity of singlet oxygen to be determined, and the criteria to distinguish between cytotoxicity and signalling of this particular ROS to be defined. The genetic basis of singlet-oxygen-mediated signalling has been revealed by the mutation of two nuclear genes encoding the plastid proteins EXECUTER (EX)1 and EX2, which are sufficient to abrogate singlet-oxygen-dependent stress responses.

Snowy cotyledon 2: the identification of a zinc finger domain protein essential for chloroplast development in cotyledons but not in true leaves.

In cotyledons of etiolated seedlings light-dependent transformation of etioplasts to chloroplasts marks the transition from heterotrophic to autotrophic growth. Genetic factors required for this developmental step were identified by isolating mutants of Arabidopsis thaliana that were impaired in chloroplast development in cotyledons but not in true leaves. Several mutants with chlorophyll-deficient cotyledons were isolated and dubbed snowy cotyledon (sco).