No abstract

It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

Summary Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11bhigh cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dpendent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain and loss of function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion, and is necessary for long-term maintenance of the mammary gland.

Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in IntroductionDyskeratosis congenita (DC) is a congenital disease that in one comprehensive population-based study was found to represent up to 5% of all bone marrow failure disorders. 1 Patients with this disease typically present in the first decade of life with a classic triad of phenotypes, including nail dystrophy, oral leukopathies, and hyperpigmentation of the skin. 2 More than 90% of all DC patients will experience cytopenia before the age of 20. 3 Other phenotypes reminiscent of aging may develop later in life, including premature graying of the hair, alopecia, taurodant teeth, and osteoporosis. [4][5][6] Although the majority of DC patients die from bone marrow failure, an increased risk of malignancy also contributes to DC mortality. 7 The genotypes of DC vary as widely as the phenotypes and encompass genes that are, with one exception, involved in the H/ACA RNP complex and/or telomere maintenance. Dyskerin (DKC1) was the first H/ACA complex gene linked to DC, the X-linked form of which has been implicated in the more severe cases of DC. 8 DKC1 mutations have also been linked to HoyeraalHreidarsson syndrome, 9 which is now considered to be an extreme form of DC with an earlier onset and a shorter life expectancy. Mutations in 2 other H/ACA RNP complex genes, NHP2 5 and NOP10, 10 have also been linked to DC patients. Two subunits of the telomerase complex, telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC), together function in the de novo synthesis of telomere ends, 11 and mutations in each component have been described in DC patients, although in general the phenotypes of these patients are relatively milder than those linked to DKC1 mutations. [12][13][14] Other mutations in genes coding for proteins that either protect telomere ends or assist in the trafficking of telomerase to Cajal bodies, TINF2 and TCAB1, respectively, have also been identified. 15,16 One protein of unknown function, C16orf57, has also recently been linked to DC, and these are the only patients that do not display shortened telomere lengths. 17 Importantly, although most of the genotypes of DC identified to date have been single amino acid substitutions, it has recently been shown that a decrease in expression of DKC1, in lieu of any gene mu...