mTORC2 Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression.

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside synthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in Luminal breast cancer-specific MCF-7 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian Luminal breast cancer patient samples, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.

Dermatan Sulfate Affects Breast Cancer Cell Function via the Induction of Necroptosis

Dermatan sulfate (DS) is widespread in the extracellular matrix (ECM) of animal tissues. This glycosaminoglycan is characterized by a variable structure, which is reflected in the heterogeneity of its sulfation pattern. The sulfate groups are responsible for the binding properties of DS, which determine an interaction profile of this glycan. However, the detailed role of DS in biological processes such as the neoplasm is still poorly understood. The aim of the study was to assess the effects of the structural variants of DS on breast cancer cells. We found that DS isoforms from normal and fibrotic fascia as well as from intestinal mucosa were able to quickly induce oxidative stress in the cytoplasm and affect the mitochondrial function in luminal breast cancer cells. Moreover, the variants caused the necroptosis of the cells most likely via the first of these mechanisms. This death was responsible for a reduction in the viability and number of breast cancer cells. However, the dynamics and intensity of all of the DS variants-triggered effects were strongly dependent on the cell type and the structure of these molecules. The most pronounced activity was demonstrated by those variants that shared structural features with the DS from the tumor niche.

New insights in the interaction of FGF/FGFR and steroid receptor signaling in breast cancer

Luminal breast cancer (BrCa) has a favorable prognosis compared to other tumor subtypes. However, with time tumors may evolve and lead to disease progression. Thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review we focused in one of the many pathways that have been involved in tumor progression, the FGF/FGFR axis. We emphasized in data obtained from in vivo experimental models since we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlighted the most frequent alterations found in BrCa cell lines and we provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. The analysis of this data suggests that there are many players involved in this pathway that might be also targeted to decrease FGF signaling in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

Clinical case of the treatment of metastatic luminal breast cancer

Hormone therapy currently open up the prospect of long-term, comfortable and relatively low-toxic treatment for patients with hormone receptor – positive advanced breast cancer. For a long time, the presence of visceral metastases prompted oncologists to abandon hormone therapy in favor of cytostatic agents. Now days, even in the presence of visceral metastases, clinical guidelines allow use of modern hormonal therapy in the absence of a visceral crisis. In particular, the so-called CDK 4/6 inhibitors, presented on the Russian market by drugs: palbociclib, ribociclib and abemacyclib, became the drugs that significantly improved the results of hormone therapy. Each of them has demonstrated its effectiveness in clinical trials; moreover, there are lots of clinical cases demonstrating the benefits of this therapy in real clinical practice. The article presents a clinical case of treatment of advanced hormone receptor-positive breast cancer. The effectiveness of treatment with CDK 4/6 inhibitors has been demonstrated, a comparatively analysed with the data obtained in the course of clinical trials. The analysis of the tactics of treatment of cytomegalovirus infection of the cornea during therapy with ribociclib was carried out.

Surgery to Oligometastatic Breast Cancer after Excellent Response to Palbociclib and Letrozole Therapy: Pitfall of Ultrasound Therapeutic Evaluation

A 48-year-old woman with regional recurrences of breast cancer in the axillar and supraclavicular regions was referred to our hospital. Under the diagnosis of recurrent luminal breast cancer with a high Ki-67 labeling index of >30% and a disease-free interval of 13 years, the patient began to receive palbociclib, letrozole, and luteinizing hormone-releasing hormone agonist, resulting in marked response of the supraclavicular lesion and stable disease of the axillar lesion on ultrasound (US) evaluation. Positron emission tomography (PET)/computed tomography of the axillar and supraclavicular foci showed high and no avidities before and after treatment, respectively. The unmovable neck lesion became movable with the treatment. The patient, therefore, underwent surgical resection of the 2 metastatic foci to examine the discordant therapeutic efficacy against the 2 metastatic foci on 2 image modalities, that is, US and PET, and to possibly get a cure of the breast cancer oligometastasis. Pathological examination showed marked fibrosis and scant cancer cell residuals with microcalcifications in the neck tumor and massive sarcoid-like reaction with scant cancer cell residuals in the axillary nodes. The residual cancer cells showed estrogen and progesterone receptor positivities, human epidermal growth factor receptor type 2 negativity, and an extremely low Ki-67 labeling index of 2.5%. The patient recovered uneventfully and has continued palbociclib-containing endocrine therapy for 1 year without any recurrences. Breast oncologists should well understand the basic principles of internal echo formation on US and take the presence of sarcoid-like reaction in the cancer cell clusters into consideration on the therapeutic evaluation of metastatic breast cancer.

Association Between RSK2 and Clinical Indexes of Primary Breast Cancer: A Meta-Analysis Based on mRNA Microarray Data

Background: Although ribosomal protein S6 kinases, 90 kDa, polypeptide 3 (RSK2, RPS6KA3) has been reported to play an important role in cancer cell proliferation, invasion, and migration, including breast cancer, its clinical implication in primary breast cancer patients is not well understood, and there were not many studies to explore the relationship between RSK2 and breast cancer on a clinical level.Methods: A systematic series matrix file search uploaded from January 1, 2008 to November 31, 2017 was undertaken using ArrayExpress and Gene Expression Omnibus (GEO) databases. Search filters were breast cancer, RNA assay, and array assay. Files eligible for inclusion met the following criteria: a) sample capacity is over 100, b) tumor sample comes from unselected patient’s primary breast tumor tissue, and c) expression of RSK2 and any clinical parameters of patients were available from the files. We use median as the cutoff value to assess the association between the expression of RSK2 and the clinical indexes of breast cancer patients.Finding: The meta-analysis identified 13 series matrix files from GEO database involving 3,122 samples that come from patients’ primary breast cancer tissue or normal tissue. The expression of RSK2 in tumor tissues is lower than that in normal tissues [odds ratio (OR), 0.54; 95% credible interval (CI), 0.44–0.67; Cochran’s Q test p = 0.14; I2 = 41.7%]. Patients with a high expression of RSK2 showed more favorable overall survival [hazard ratio (HR), 0.71; 95% CI, 0.49–0.94; Cochran’s Q test p = 0.95; I2 = 0.0%] and less potential of distant metastasis (OR, 0.59; 95% CI, 0.41–0.87; Cochran’s Q test p = 0.88; I2 = 0.0%) and lymph node infiltration (OR, 0.81; 95% CI, 0.65–0.998; Cochran’s Q test p = 0.09; I2 = 42.8%). Besides, the expression of RSK2 in luminal breast cancer is lower than Cochran’s Q test p = 0.06; I2 = 63.5%). RSK2 overexpression corresponded with higher histological grade (OR, 1.329; 95% CI, 1.03–1.721; Cochran’s Q test p = 0.69; I2 = 0.0%). RSK2 expression is also associated with estrogen receptor (ER) and age.Conclusion: The meta-analysis provides evidence that RSK2 is a potential biomarker in breast cancer patients. The expression of RSK2 is distinctive in different intrinsic subtypes of breast cancer, indicating that it may play an important role in specific breast cancer. Further study is needed to uncover the mechanism of RSK2 in breast cancer.Systematic Review Registration: (website), identifier (registration number).

Histone Variant H2A.J Is Enriched in Luminal Epithelial Gland Cells

H2A.J is a poorly studied mammalian-specific variant of histone H2A. We used immunohistochemistry to study its localization in various human and mouse tissues. H2A.J showed cell-type specific expression with a striking enrichment in luminal epithelial cells of multiple glands including those of breast, prostate, pancreas, thyroid, stomach, and salivary glands. H2A.J was also highly expressed in many carcinoma cell lines and in particular, those derived from luminal breast and prostate cancer. H2A.J thus appears to be a novel marker for luminal epithelial cancers. Knocking-out the H2AFJ gene in T47D luminal breast cancer cells reduced the expression of several estrogen-responsive genes which may explain its putative tumorigenic role in luminal-B breast cancer.

FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.