Fez1/Lzts1 a new mitotic regulator implicated in cancer development

Considerable evidence has accumulated suggesting that cancer has genetic origin, based on the development of genomic alterations, such as deletions, mutations, and/or methylations in critical genes for homeostasis of cellular functions, including cell survival, DNA replication and cell cycle control. Mechanism controlling the precise timing and sequence of cell cycle events as well as checkpoints insuring fidelity of those events are key targets that when disrupted could result in tumorigenesis. Mitosis is the process by which a cell duplicates its genetic information (DNA), in order to generate two, identical, daughter cells. In addition each daughter cell must receive one centrosome and the appropriate complements of cytoplasm and organelles. This process is conventionally divided in to five distinct stages: prophase, prometaphase, metaphase, anaphase and telophase that correspond to a different morphology of the cell. The entry into mitosis (M) is under the control of the cyclin dependent kinase Cdk1. During G2, the kinases Wee1 and Myt1 phosphorylate Cdk1 at T14/Y15 residues, rendering it inactive. The transition from G2 to M is promoted by the activation of Cdk1 via dephosphorylation by the Cdk1 phosphatase Cdc25C. Activated Cdk1 complexes translocate into the nucleus during prophase where phosphorylate numerous substrates in order to enhance their activation as the cells progresses trough prophase, prometaphase, and metaphase

HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel

High Mobility Group A1 (HMGA1) is an architectural chromatin factor involved in the regulation of gene expression and a master regulator in Triple Negative Breast Cancer (TNBC). In TNBC, HMGA1 is overexpressed and coordinates a gene network that controls cellular processes involved in tumour development, progression, and metastasis formation. Here, we find that the expression of HMGA1 and of the microtubule-destabilizing protein stathmin correlates in breast cancer (BC) patients. We demonstrate that HMGA1 depletion leads to a downregulation of stathmin expression and activity on microtubules resulting in decreased TNBC cell motility. We show that this pathway is mediated by the cyclin-dependent kinase inhibitor p27(kip1) (p27). Indeed, the silencing of HMGA1 expression in TNBC cells results both in an increased p27 protein stability and p27-stathmin binding. When the expression of both HMGA1 and p27 is silenced, we observe a significant rescue in cell motility. These data, obtained in cellular models, were validated in BC patients. In fact, we find that patients with high levels of both HMGA1 and stathmin and low levels of p27 have a statistically significant lower survival probability in terms of relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with respect to the patient group with low HMGA1, low stathmin, and high p27 expression levels. Finally, we show in an in vivo xenograft model that depletion of HMGA1 chemo-sensitizes tumour cells to paclitaxel, a drug that is commonly used in TNBC treatments. This study unveils a new interaction among HMGA1, p27, and stathmin that is critical in BC cell migration. Moreover, our data suggest that taxol-based treatments may be more effective in reducing the tumour burden when tumour cells express low levels of HMGA1

Landscape of CDKN1B Mutations in Luminal Breast Cancer and Other Hormone-Driven Human Tumors

The CDKN1B gene encodes for the p27Kip1 protein, firstly characterized as a cyclin dependent kinase (CDK)-inhibitor. Germline CDKN1B pathogenic variants have been described in hereditary tumors, such as multiple endocrine neoplasia (MEN)-like syndromes and familial prostate cancer. Despite its central role in tumor progression, for a long time it has been proposed that CDKN1B was very rarely somatically mutated in human cancer and that its expression levels were almost exclusively regulated at post-transcriptional level. Yet, the advent of massive parallel sequencing has partially subverted this general understanding demonstrating that, at least in some types of cancer, CDKN1B is mutated in a significant percentage of analyzed samples. Recent works have demonstrated that CDKN1B can be genetically inactivated and this occurs particularly in sporadic luminal breast cancer, prostate cancer and small intestine neuroendocrine tumors. However, a clear picture of the extent and significance of CDKN1B mutations in human malignances is still lacking. To fill this gap, we interrogated the COSMIC, ICGC, cBioPortal, and TRANSFAC data portals and current literature in PubMed, and reviewed the mutational spectrum of CDKN1B in human cancers, interpreting the possible impact of these mutations on p27Kip1 protein function and tumor onset and progression

Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer

miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells, miR-223 acted cell autonomously in the control of their growth and morphology in three-dimensional context. In the MMTV-Δ16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from patients with luminal and HER2-positive breast cancer. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy. SIGNIFICANCE: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer

SRSF2 mutations in epithelial ovarian cancer

Resistance to platinum chemotherapy regimens represents a major obstacle in the successful treatment of epithelial ovarian cancer (EOC) patients. Among the molecular mechanism responsible for resistance to platinum, alternative splicing, which is induced upon platinum treatment, can control apoptosis by regulating the expression of apoptotic protein variants with opposite functions. Alterations in alternative splicing are found in tumors and can hinder apoptotic response. In the present study we sequenced SRSF2, a splicing factor that regulates Caspase-8 and Caspase-9 variants, in search of mutations that could possibly explain alternative mechanisms of platinum resistant in EOC

Loss of CDKN1B induces an age‐related clonal hematopoietic disorder via Notch2 activity dysregulation

No abstract availabl

Author Correction: Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth

Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutation