No abstract

Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

Key Points ACTN1 mutations were identified in 10 of 239 families with inherited thrombocytopenia of unknown origin. ACTN1-related thrombocytopenia is characterized by mild thrombocytopenia with platelet macrocytosis and low risk for bleeding.

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 x 10 9 /L. ABSTRACT antepartum intracranial hemorrhage. On this basis, it has been concluded that bBSS is associated with a very high risk of serious bleeding in the mother and the neonate. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopeniaSome information on pregnancy outcome is available also for MYH9-related disease (MYH9-RD), one of the most frequent forms of IT. A recent review of the literature examined 25 case reports and one case series describing a total of 75 pregnancies in 40 women.5 Postpartum hemorrhage in the mother occurred in 4 cases, while no obvious bleeding complications were reported among the newborns. Based on these data, MYH9-RD does not seem to increase bleeding risk either in mothers or neonates.Limited data on pregnancy outcomes have been provided for patients with mild to moderate thrombocytopenia due to monoallelic BSS (mBSS), in all cases induced by the p.Ala156Val substitution in GPIb alpha (Bolzano mutation). 6 Overall, 20 women delivered 34 children with no excessive maternal or neonatal bleeding. Although the authors did not provide information on management of pregnancies and childbirths, this study suggests that women with mBSS have gestational outcomes similar to healthy subjects.A moderate risk of bleeding during delivery has been reported in a series of subjects with thrombocytopenia induced by ANKRD26 mutations (ANKRD26-related thrombocytopenia, ANKRD26-RT).7 Thirteen patients gave birth, either vaginally or by caesarean section, with bleeding complications in 3 women. No information was provided o...