An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer.

Lymphovascular invasion (LVI) is associated with a poor outcome in breast cancer. The purpose of the present study was to evaluate the clinical significance of LVI in primary breast cancer and to investigate disease-free survival as a prognostic marker according to the breast cancer subtypes. This study examined 4,652 consecutive cases of invasive breast cancer excluding the patients with non-invasive cancer, stage IV and those who underwent neo-adjuvant therapy from February 2002 to February 2021. The clinicopathological characteristics and prognosis of LVI-positive and -negative tumors were compared. LVI was evaluated in H&E staining specimens from surgically resected samples. The LVI expression rates were 29.2% (low, 19.7%; high, 9.5%) in all primary cases. The LVI-positive rate was significantly associated with specimens with the following characteristics: ER/PgR-negative, HER2-positive, p53 overexpression, higher Ki-67 index values, higher nuclear grade, positive nodes and larger tumors. Moreover, the subtypes were significantly associated with LVI positivity; 20% in Luminal A, 34.6% in Luminal B, 40.9% in Lumina/HER2, 38.1% in HER2-enriched and 29.8% in triple negative (TN). There were significant differences in disease-free survival between LVI status in Luminal A, Luminal B and TN subtypes, but there was no difference in the Luminal/HER2 and HER2-enriched subtypes. A multivariate analysis revealed that LVI was a significant factor in Luminal B and TN subtypes. Overall, LVI was significantly associated with the advanced and aggressive characteristics in breast cancer. Luminal A type had a lower LVI rate, and HER2 type had a higher LVI rate. Moreover, LVI was a significant prognostic factor in Luminal B and TN subtypes. These data suggested that the LVI status was useful in predicting the prognosis in HER2 negative breast cancer cases.

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3ß at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-ß-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gß and 4.0% of PI3Kß, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.

The FBI1/Akirin2 target gene, BCAM, acts as a suppressive oncogene.

Basal cell adhesion molecule (BCAM), known to be a splicing variant of Lutheran glycoprotein (LU), is an immunoglobulin superfamily membrane protein that acts as a laminin α5 receptor. The high affinity of BCAM/LU for laminin α5 is thought to contribute to the pathogenesis of sickle red blood cells and to various developmental processes. However, the function of BCAM in carcinogenesis is poorly understood. Based on microarray expression analysis, we found that BCAM was one of the target genes of the oncogenic 14-3-3ß-FBI1/Akirin2 complex, which acts as a transcriptional repressor and suppresses MAPK phosphatase-1 gene expression. To elucidate the detailed function of BCAM in malignant tumors, we established BCAM-expressing hepatoma K2 cells. These cells lost the malignant characteristics of parental cells, such as anchorage-independent growth, migration, invasion, and tumorigenicity. Moreover, luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the 14-3-3ß-FBI1/Akirin2 complex bound to the BCAM promoter and repressed transcription. Thus, these data indicate that BCAM is a suppressive oncoprotein, and that FBI1/Akirin2 is involved in tumorigenicity and metastasis of hepatoma through the downregulation of suppressive oncogenes.