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View the Table of Contents for the October 1 issue of Cancer Research.
Teh et al. Page 8597
Loss of heterozygosity (LOH) and allelic imbalance are both hallmarks of genomic instability in cancers. Teh et al. employed a 10K SNP microarray for fingerprinting genomic instability in basal cell carcinoma (BCC), the most common form of human cancer. In addition to allelic imbalance, this mapping technique unveiled a phenomenon, uniparental disomy (UPD), causing LOH without allelic imbalance. Both UPD and allelic imbalance were found to contribute to LOH at 9q21-q31 in 93% of BCCs studied. This fingerprinting technique advances our understanding in cancer genomics where UPD was found to be a smokeless weapon in causing LOH.
Prasad et al. Page 8655
Loss of one copy of the Atp2a2 gene encoding SERCA2, the major endoplasmic reticulum Ca2+ pump, causes squamous cell tumors in mice and Darier disease in humans, both involving keratinocytes. Using laser capture microdissection, immunohistochemistry, and immunoblotting, Prasad et al. showed prelesional changes in keratin expression indicative of altered differentiation of keratinized epithelia. The retention of the wild-type Atp2a2 allele was coupled with increased expression of wild-type ras genes in the tumors. These data indicate that the perturbation of Ca2+ handling resulting from Atp2a2 haploinsufficiency represents a novel mode of cancer susceptibility involving a tissue-level predisposition to tumor development.
Yang et al. Page 8671
Smad4 is the common mediator of transforming growth factor-β signaling. To study the role of Smad4 in skin development, Yang et al. generated a keratinocyte-specific null mutant of Smad4 in mice using the Cre-loxP system. The Smad4-mutant mice exhibited progressive alopecia as a result of the mutant hair follicles failing to undergo programmed regression, and early onset of skin neoplasia, indicating that Smad4 is essential for catagen induction and acts as a critical suppressor in skin tumorigenesis. Importantly, they provided the first in vivo genetic evidence that Smad4 and PTEN act synergistically to negatively regulate epidermal proliferation and differentiation.
Bowen et al. Page 8736
A role of ATM carrier status in familial breast cancer has been controversial and difficult to address in humans. Bowen et al. used the conditional loss of murine Brca1 exon 11 model of mammary gland epithelial tumors (Brca1-MG-Dex11) that were either wild-type or heterozygous for an Atm null allele. Brca1-MG-Dex11; Atm heterozygotes displayed tumors that were more undifferentiated than Brca1-MG-Dex11; Atm wild-type mice. Atm heterozygotes also displayed defects in ductal branching. Thus, Atm heterozygosity influences severity of mammary gland tumors in Brca1-MG-Dex11 tumor-prone mice, which suggests that this mutation leads to a newly characterized developmental defect during glandular maturation.
Locke et al. Page 8944
Malignant stem cells appear to form the necessary targets of cancer therapy, but little is known about their properties. Locke et al. demonstrate that persistence of a hierarchical stem cell pattern in carcinoma cell lines produces a range of colony morphologies that predict differing growth potentials and expression profiles of their constituent cells. An altered asymmetric division pattern is necessary for the continuous stem cell expansion associated with malignancy and the retention of basic stem cell behavior in vitro should facilitate studies directed towards the molecular and pharmacological manipulation of malignant stem cell survival.