High expression levels of p27 correlate with lymph node status in a subset of advanced invasive breast carcinomas - Relation to E-cadherin alterations, proliferative activity, and ploidy of the tumors

BACKGROUND. The cyclin-dependent kinase inhibitor p27 plays a central role in cell cycle progression and is deregulated in breast carcinomas. Although its levels are inversely associated with tumor proliferation, overexpression of p27 has been reported in a subset of rapidly proliferating breast carcinoma cell lines. METHODS. p27 levels were determined by immunohistochemistry in a series of 52 sporadic invasive breast carcinomas consisting of 47 ductal, 2 lobular, and 3 mixed; most tumors were Grade 2 or 3 (46 of 52) and Tumor Node Metastasis (TNM) Stage II-IV (46 of 52). E-cadherin expression and its gene alterations at 16q22.1 were also studied, because in vitro evidence suggests a biologic association between p27 and E-cadherin-mediated growth suppression. RESULTS. The mean p27 labeling index (LI; percentage of p27 positive tumor cells) was 33.3% +/- 25.3% (range, 0.1-85%). High p27 levels (p27 LI, > 50%) were observed in 14 (26.9%) of 52 carcinomas and were significantly associated with metastatic disease in axillary lymph nodes (14 of 33 vs. 0 of 19; P = 0.0007 by Fisher exact test). In addition, p27 LI was higher in the group of lymph node positive vs. lymph node negative tumors (mean p27 LI, 40.9% vs. 20.1%; P = 0.008 by Mann-Whitney test). Reduced or absent E-cadherin expression was found in 27 of 45 (60%) informative cases. Allelic imbalance of the 16q22.1 locus was found in 14 (27.5%) of 51 cases by using the microsatellite markets D16S503, D16S752, and D16S512. p27 LI and E-cadherin alterations were not statistically related. CONCLUSIONS. in summary, high p27 levels detected in a subset of advanced breast carcinomas correlate with lymph node metastasis, suggesting that other mechanisms may bypass the cell cycle inhibitory role or p27 and provide growth advantage in these tumors. (C) 2002 American Cancer Society

SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development

The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development

Glycine receptors control the generation of projection neurons in the developing cerebral cortex

The development of the cerebral cortex requires coordinated regulation of proliferation, specification, migration and differentiation of cortical progenitors into functionally integrated neurons. The completion of the neurogenic program requires a dynamic interplay between cell intrinsic regulators and extrinsic cues, such as growth factor and neurotransmitters. We previously demonstrated a role for extrasynaptic glycine receptors (GlyRs) containing the α2 subunit in cerebral cortical neurogenesis, revealing that endogenous GlyR activation promotes interneuron migration in the developing cortical wall. The proliferative compartment of the cortex comprises apical progenitors that give birth to neurons directly or indirectly through the generation of basal progenitors, which serve as amplification step to generate the bulk of cortical neurons. The present work shows that genetic inactivation of Glra2, the gene coding the α2 subunit of GlyRs, disrupts dorsal cortical progenitor homeostasis with an impaired capability of apical progenitors to generate basal progenitors. This defect results in an overall reduction of projection neurons that settle in upper or deep layers of the cerebral cortex. Overall, the depletion of cortical neurons observed in Glra2-knockout embryos leads to moderate microcephaly in newborn Glra2-knockout mice. Taken together, our findings support a contribution of GlyR α2 to early processes in cerebral cortical neurogenesis that are required later for the proper development of cortical circuits