mercredi 6 février 2013

Mutated genes in cancer (85) –PALB2 (FANCN)





PALB2 (alias FANCN)

In databases :

Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 79728 or PALB2
Ensembl (http://www.ensembl.org/index.html): ENSG00000083093
UniProt (http://www.uniprot.org/): Q86YC2
OMIM (http://www.ncbi.nlm.nih.gov/omim): 610355
GeneCards (http://www.genecards.org/): PALB2
HGNC (http://www.genenames.org/): 26144 or PALB2

Gene locus :

16p12.2

Protein name:

Partner and localizer of BRCA2

Protein Size:

1186 amino acids; about 131 kDa

Function:

This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. It also enables the recombinational repair and checkpoint functions of BRCA2.

Cancer-related alterations:

Genetic variations in PALB2 are associated with breast cancer susceptibility.

Defects in PALB2 are the cause of Fanconi anemia complementation group N (FANCN)
(see Fanconi Anemia genes)

Somatic PALB2 point mutations are rare.

References (open access):

A PALB2 mutation associated with high risk of breast cancer. Southey MC, Teo ZL, Dowty JG, Odefrey FA, Park DJ, Tischkowitz M, Sabbaghian N, Apicella C, Byrnes GB, Winship I, Baglietto L, Giles GG, Goldgar DE, Foulkes WD, Hopper JL; kConFab for the Beast Cancer Family Registry. Breast Cancer Res. 2010;12(6):R109.

PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Zhang F, Fan Q, Ren K, Andreassen PR. Mol Cancer Res. 2009 Jul;7(7):1110-8.

Germline mutations and polymorphisms in the origins of cancers in women. Hirshfield KM, Rebbeck TR, Levine AJ. J Oncol. 2010;2010:297671.


Focus: Behavioral stress accelerates prostate cancer development in mice




Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress-prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog-deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling

Source: Behavioral stress accelerates prostate cancer development in mice. Hassan S, Karpova Y, Baiz D, Yancey D, Pullikuth A, Flores A, Register T, Cline JM, D'Agostino R Jr, Danial N, Datta SR, Kulik G (gkulik@wakehealth.edu). J Clin Invest. 2013 Jan 25. pii: 63324.
Free paper available at:

mardi 5 février 2013

Focus: Important miRs of Pathways in Different Tumor Types




We computationally determined miRs that are significantly connected to molecular pathways by utilizing gene expression profiles in different cancer types such as glioblastomas, ovarian and breast cancers. Specifically, we assumed that the knowledge of physical interactions between miRs and genes indicated subsets of important miRs (IM) that significantly contributed to the regression of pathway-specific enrichment scores. Despite the different nature of the considered cancer types, we found strongly overlapping sets of IMs. Furthermore, IMs that were important for many pathways were enriched with literature-curated cancer and differentially expressed miRs. Such sets of IMs also coincided well with clusters of miRs that were experimentally indicated in numerous other cancer types. In particular, we focused on an overlapping set of 99 overall important miRs (OIM) that were found in glioblastomas, ovarian and breast cancers simultaneously. Notably, we observed that interactions between OIMs and leading edge genes of differentially expressed pathways were characterized by considerable changes in their expression correlations. Such gains/losses of miR and gene expression correlation indicated miR/gene pairs that may play a causal role in the underlying cancers.

Source: Important miRs of Pathways in Different Tumor Types. Wuchty S (wuchtys@ncbi.nlm.nih.gov), Arjona D, Bauer PO. PLoS Comput Biol. 2013 Jan;9(1):e1002883.
Free paper available at:

lundi 4 février 2013

Focus: β4 Integrin signaling induces expansion of prostate tumor progenitors





Abstract
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.

Source: β4 Integrin signaling induces expansion of prostate tumor progenitors. Yoshioka T, Otero J, Chen Y, Kim YM, Koutcher JA, Satagopan J, Reuter V, Carver B, de Stanchina E, Enomoto K, Greenberg NM, Scardino PT, Scher HI, Sawyers CL, Giancotti FG (f-giancotti@ski.mskcc.org). J Clin Invest. 2013 Jan 25.
Free paper available at:

Focus: The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers



SWI/SNF is a multi-subunit chromatin remodeling complex that uses the energy of ATP hydrolysis to reposition nucleosomes, thereby modulating gene expression. Accumulating evidence suggests that SWI/SNF functions as a tumor suppressor in some cancers. However, the spectrum of SWI/SNF mutations across human cancers has not been systematically investigated. Here, we mined whole-exome sequencing data from 24 published studies representing 669 cases from 18 neoplastic diagnoses. SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations.

Source: The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. Shain AH, Pollack JR.  PLoS One. 2013;8(1):e55119.
Free paper available at:

vendredi 1 février 2013

Press Review (February 2, 2013) – Revue de presse (2 février 2013)




Celsion's liver cancer therapy fails to meet late-stage trial goal
Celsion Corp said a late-stage study of its experimental liver cancer treatment ThermoDox did not meet the main goal of increasing patients' survival without their cancer worsening.
In Reuters

RNA Fragments May Yield Rapid, Accurate Cancer Diagnosis
A new method to noninvasively diagnose cancer and monitor its progression could eliminate the need for painful and sometimes life-threatening biopsies.
By William Ferguson. In Scientific American

When It Comes to Breast Cancer, Less May Be More!
It may seem counter intuitive, but even when it come to breast cancer treatment, the saying may stand: Less is more!.
By Leigh Vinocur. In Huffington Post

New Target to Stop Cancer's Spread
Disrupting a key interaction between two types of proteins in cells inhibits the spread of cancerous cells, providing researchers with a new pathway toward developing cancer-fighting drugs, according to new findings by Georgia State University scientists.
In Science Daily

How the tilt of a cell-surface receptor prevents cancer
Clear communication between cells is essential to every aspect of the body's internal function. But since cells can't talk, or send emails, how do they communicate?
In EurekAlert (press release)

Lumpectomy With Radiation Linked With Better Breast Cancer Survival Rates Than Mastectomy: Study
A new study from Duke University researchers shows that early stage breast cancer patients may actually fare better if they don't undergo surgery to have their breasts removed, and instead undergo a less-invasive treatment.
In Huffington Post

'Master' Proto-Oncogene Regulates Stress-Induced Ovarian Cancer Metastasis
Scientists at The University of Texas MD Anderson Cancer Center have discovered the signaling pathway whereby a master regulator of cancer cell proteins -- known as Src -- leads to ovarian cancer progression when exposed to stress hormones. The researchers report in the current issue of Nature Communications that beta blocker drugs mitigate this effect and reduce cancer deaths by an average of 17 percent.
In Science Daily

Qi Gong Could Improve Breast Cancer Patients' Quality Of Life
An ancient Chinese practice could make life better for women undergoing treatment for breast cancer, according to a small new study.
In Huffington Post

Deep-Fried Foods Associated With Higher Prostate Cancer Risk
Here's news that might make you want to take it easy on the fries.
In Huffington Post



Traitement du cancer : pourrait-on faire beaucoup mieux ?
Il serait possible de guérir tous les cancers si la recherche contre cette maladie était moins sclérosée, selon un chercheur.
Par Anne Jeanblanc. Dans Le Point

Bière : Et si elle était un bon remède contre le cancer et le diabète ?
Selon des chercheurs de l'Université de Washington, la bière et ses acides amers, avec modération, ont des effets bénéfiques sur le diabète, certaines formes de cancer, de l'inflammation et peut-être même la perte de poids
Dans Atlantico.fr

Cancer du sein : un bon point pour la tumorectomie au stade précoce
Dans le choix difficile entre tumorectomie et mastectomie au stade précoce, une étude américaine publiée dans Cancer pourrait peser fortement en faveur de la chirurgie conservatrice.
Dans Le Quotidien du Médecin

Le risque de cancer augmente près des usines de déchets électroniques
Les appareils électroniques agrémentent notre quotidien puis s’en vont dans les pays en développement pour y être incinérés. Leur combustion libère des hydrocarbures aromatiques polycycliques (HAP) cancérigènes. En Chine, le risque de cancer du poumon est 1,6 fois plus important pour les habitants proches des usines de traitement que pour les habitants des villes, pourtant plus polluées, mais par d’autres industries.
Par Delphine Bossy. Dans Futura-Sciences



Focus: Regional activation of the cancer genome by long-range epigenetic remodeling




Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within LREA domains are characterized by a gain of active chromatin marks and a loss of repressive marks. Notably, although promoter hypomethylation is uncommon, we show that extensive DNA hypermethylation of CpG islands or "CpG-island borders" is strongly related to cancer-specific gene activation or differential promoter usage. These findings have wide ramifications for cancer diagnosis, progression, and epigenetic-based gene therapies.

Source: Regional activation of the cancer genome by long-range epigenetic remodeling. Bert SA, Robinson MD, Strbenac D, Statham AL, Song JZ, Hulf T, Sutherland RL, Coolen MW, Stirzaker C, Clark SJ. Cancer Cell. 2013 Jan 14;23(1):9-22.
Free paper available at: