Publisher Correction: Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer.

The original version of this Article contained an error in Fig. 4. In the left histogram of the right panel of Fig. 4d, several data points were inadvertently deleted from the histogram during the production process. This error has been corrected in both the PDF and HTML versions of the Article. The original, incorrect version of Fig. 4 is presented in the accompanying Publisher Correction.

Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer.

Primary triple negative breast cancers (TNBC) are prone to dissemination but sub-clonal relationships between tumors and resulting metastases are poorly understood. Here we use cellular barcoding of two treatment-naïve TNBC patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands of barcoded clones in primary tumors, and their metastases. Tumor resection had a major impact on reducing clonal diversity in secondary sites, indicating that most disseminated tumor cells lacked the capacity to 'seed', hence originated from 'shedders' that did not persist. The few clones that continued to grow after resection i.e. 'seeders', did not correlate in frequency with their parental clones in primary tumors. Cisplatin treatment of one BRCA1-mutated PDX model to non-palpable levels had a surprisingly minor impact on clonal diversity in the relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of shedding, seeding and drug resistance are important factors to consider for the design of therapeutic strategies.

FGFR1 inhibition in lung squamous cell carcinoma: questions and controversies.

Although the incidence of lung cancer has decreased due to the reduction of tobacco use, lung cancer remains the leading cause of cancer-related death. Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene amplification and genetic alterations in the phosphoinositide-3 kinase pathway. These discoveries have generated a great interest in the clinic and the initiation of clinical trials using FGFR tyrosine kinase inhibitors to treat FGFR-altered lung cancers. However, preliminary results from these studies have shown that not all patients respond to therapy. Here we review current unresolved questions on the selection of patients for their recruitment in FGFR tyrosine kinase inhibitor trials, how FGFR inhibitors could be combined with other targeted therapies or immunotherapies to improve patient outcome, and how the current preclinical models can help address these questions.

Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2.

Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit.

Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitor-like expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1(Co/Co) mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61(+)CD29(lo)CD24(+)) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

Delineating the epithelial hierarchy in the mouse mammary gland.

Reconstitution assays have shown that mouse mammary stem cells reside within the mature mammary gland in vivo. Single cells could be prospectively isolated and shown to regenerate an entire mammary gland that exhibited full developmental capacity. The more recent identification of luminal progenitor populations has indicated that the mammary epithelium is organized in a hierarchical manner. Further definition of epithelial cell types in both mouse and human mammary glands will provide insight into the "cells of origin" in the different subtypes of breast cancer, as well as the nature of cancer-propagating cells. Here, we review the known characteristics of mammary stem and progenitor cells, their steroid receptor status, and the pathways that have thus far been implicated in regulating their self-renewal and differentiation.

Dexamethasone and IL-10 stimulate glucocorticoid-induced leucine zipper synthesis by human mast cells.

BACKGROUND: Glucocorticoids (GCs) decrease tissue mast cell (MC) number and prevent their activation via their high-affinity IgE receptor. Glucocorticoid-induced leucine zipper (GILZ) is one of the GC-induced genes, which inhibits the functions of the transcriptional activators AP-1 and NF-kappaB. GILZ appears to be a critical actor in the anti-inflammatory and immunosuppressive effects of GCs in human T lymphocytes, macrophages and dendritic cells. AIMS OF THE STUDY: We investigated whether GILZ was produced by human MCs and whether GILZ synthesis was stimulated by GCs. We also investigated whether GILZ production was modulated by (i) IL-10, because of its common immunosuppressive properties with GCs, (ii) histamine because of its pro-inflammatory properties and (iii) IL-4 and IL-5 because of their ability to favour MC survival and proliferation with SCF. METHODS: The human MC lines HMC-1 5C6 and LAD-2, and cord blood-derived MCs (CB-MCs) were cultured alone or in the presence of GCs, IL-10, histamine, IL-4 or IL-5. The expression of GILZ was evaluated by using RT-PCR, Western blotting or immunocytochemistry. RESULTS: We found that human MC lines and CB-MCs constitutively produce GILZ. We also show that GCs and IL-10 stimulate GILZ production by human MCs. Our present results indicate that histamine, IL-4 and IL-5 alone or in combination with SCF do not downregulate GILZ production by MCs. CONCLUSIONS: These results show that GCs and IL-10 stimulate GILZ production by human MCs. As GILZ mediates anti-inflammatory effects of GCs in immune cells, we speculate that GILZ could account for the deactivation of MCs by GCs and IL-10.