mercredi 31 août 2011

Focus : YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification.

Y-box binding protein-1 (YB-1) expression in the mammary gland promotes breast carcinoma that demonstrates a high degree of genomic instability. In the present study, we developed a model of pre-malignancy to characterize the role of this gene during breast cancer initiation and early progression. Antibody microarray technology was used to ascertain global changes in signal transduction following the conditional expression of YB-1 in human mammary epithelial cells (HMEC). Cell cycle-associated proteins were frequently altered with the most dramatic being LIM kinase 1/2 (LIMK1/2). Consequently, the misexpression of LIMK1/2 was associated with cytokinesis failure that acted as a precursor to centrosome amplification. Detailed investigation revealed that YB-1 localized to the centrosome in a phosphorylation-dependent manner, where it complexed with pericentrin and γ-tubulin. This was found to be essential in maintaining the structural integrity and microtubule nucleation capacity of the organelle. Prolonged exposure to YB-1 led to rampant acceleration toward tumorigenesis, with the majority of cells acquiring numerical and structural chromosomal abnormalities. Slippage through the G(1)/S checkpoint due to overexpression of cyclin E promoted continued proliferation of these genomically compromised cells. As malignancy further progressed, we identified a subset of cells harboring HER2 amplification. Our results recognize YB-1 as a cancer susceptibility gene, with the capacity to prime cells for tumorigenesis.

Source: YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification. Davies AH, Barrett I, Pambid MR, Hu K, Stratford AL, Freeman S, Berquin IM, Pelech S, Hieter P, Maxwell C, Dunn SE ( Oncogene. 2011 Aug 25;30(34):3649-3660.

L’expression de la « Y-box binding protein-1 », ou YB-1, dans la glande mammaire favorise le carcinome mammaire avec un haut degré d'instabilité génomique. Dans la présente étude, nous avons développé un modèle précancereux pour caractériser le rôle de ce gène lors de l'initiation et de la progression précoce du cancer du sein. La technologie des biopuces à anticorps a été utilisée pour déterminer les changements globaux dans la transduction du signal consécutifs à l'expression conditionnelle de YB-1 dans les cellules épithéliales mammaires humaines. Les taux de protéines associées au cycle cellulaire furent souvent modifiés, l’altration la plus spectaculaire touchant  les LIM kinases 1 / 2 (LIMK1 / 2). Cette misexpression des LIMK1 / 2 était associée à une insuffisance de cytokinèse constituant un précurseur à l'amplification des centrosomes. Une exposition prolongée des cellules épithéliales mammaires à YB-1 conduit à une accélération dramatique vers la tumorigenèse, avec une majorité des cellules qui acquièrent des anomalies chromosomiques en nombre et en structure, et même l’apparition d’un sous-ensemble de cellules présentant une amplification d’HER2. Nos résultats reconnaissent YB-1 comme un gène de susceptibilité au cancer.

Article (en anglais) disponible à l’adresse :

mardi 30 août 2011

The twelve US (FDA) approved small molecule protein kinase inhibitors.

Other names
Cancer type

Nonreceptor tyrosine kinase inhibitor
Glivec, Gleevec
a multitargeted c-kit, PDGF-R and c-ABL inhibitor
Newly diagnosed adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase;

Patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy;

Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy;

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (ALL);
Adult patients with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements;

Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown;
Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL);
Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP);

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST);

-Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
Receptor tyrosine kinase inhibitor
Iressa, ZD-1839
EGFR and Akt inhibitor
Locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of platinum-based and docetaxel chemotherapy
Receptor tyrosine kinase inhibitor
Tarceva, CP-358774, OSI-774, NSC-718781
EGFR inhibitor
 Locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen;

Maintenance treatment of NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy;

In combination with gemcitabine for treatment of patients with locally advanced, unresectable or metastatic pancreatic carcinoma.
Receptor tyrosine kinase inhibitor
VEGFR, PDGFR and RAF/MEK/ERK cascade inhibitor
Unresectable hepatocellular carcinoma (HCC);

Advanced renal cell carcinoma (RCC)
Nonreceptor tyrosine kinase inhibitor
Sprycel, BMS-354825, BMS354825
ATP-competitive, dual SRC/ABL inhibitor. It inhibits all members of the Src family, including c-Src, Lck, Fyn, and Yes
Chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia (CP-CML);

Chronic phase (CP) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy;

Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy.
Receptor tyrosine kinase inhibitor
multitargeted FLT3, PDGFRs, VEGFRs, and Kit kinase inhibitor
Advanced renal cell carcinoma;

Gastrointestinal stromal tumor (GIST) after disease progression on, or intolerance to, imatinib mesylate
Nonreceptor tyrosine kinase inhibitor
Tasigna, AMN-107
Inhibitor of BCR-ABL
Adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP-CML);

Chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.
Receptor tyrosine kinase inhibitor
EGFR and HER2 inhibitor
Hormone-receptor- and HER2-positive advanced breast cancer;

HER2-overexpressing breast cancer
Receptor tyrosine kinase inhibitor
VEGFR-1, -2, and -3 inhibitor
Advanced renal cell carcinoma
Receptor tyrosine kinase inhibitor
VEGFR and EGFR inhibitor
Unresectable, locally advanced, or metastatic medullary thyroid cancer
Serine/threonine kinase inhibitor
Zelboraf, PLX-4032, RG7204, R7204 & RO5185426
BRAf inhibitor
Unresectable or metastatic melanoma carrying the mutant BRAFV600E.
Serine/threonine kinase inhibitor
Xalkori, PF-2341066
ALK and HGFR inhibitor
Locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by an approved FDA-approved test.

dimanche 28 août 2011

Mutated genes in cancer (10) – FLCN


In databases:

● Entrez ( 201163 or FLCN
● Ensembl ( ENSG00000154803
● UniProt ( Q8NFG4
● GeneCards ( FLCN
● HGNC ( 27310 or FLCN

Gene locus:


Protein name:


Protein Size:

579 amino acids; about 64 kDa


Folliculin forms a complex with folliculin-interacting proteins 1 and 2 (FNIP1 and FNIP2), and 5'-AMP-activated protein kinase (AMPK), an important energy sensor in cells that negatively regulates mammalian target of rapamycin (mTOR). Folliculin plays a role in the regulation of key molecules in TGF-beta signaling. Folliculin is a tumor suppressor (Hong SB et al. 2010).

Cancer-related alterations

Defects in FLCN are the cause of Birt-Hogg-Dube syndrome (BHD). BHD is a rare autosomal dominant genodermatosis characterized by hair follicle hamartomas (fibrofolliculomas), kidney tumors, and spontaneous pneumothorax. Fibrofolliculomas are part of the triad of BHD skin lesions that also includes trichodiscomas and acrochordons. Onset of this dermatologic condition is invariably in adulthood. BHD is associated with a variety of histologic types of renal tumors, including chromophobe renal cell carcinoma (RCC), benign renal oncocytoma, clear-cell RCC and papillary type I RCC. Multiple lipomas, angiolipomas, and parathyroid adenomas are also seen in patients affected with this disease. The majority of mutations are predicted to prematurely terminate the protein.

BHD syndrome is characterized by a spectrum of mutations (at least 23 different germline mutations, of various types), and clinical heterogeneity both among and within families (Toro JR et al. 2008). All germline mutations are predicted to truncate the mutant protein. Mutations are located along the entire length of the coding region, with no genotype-phenotype correlations noted between type of mutation, location within the gene and phenotypic disease manifestations. More than 50% of mutations have been observed in a “hotspot” in exon 11

FLCN/BHD somatic mutations have been found at only a very low frequency (0-10%) in sporadic renal tumors and therefore, may not represent a major mechanism for the development of sporadic renal carcinoma. Loss of 17p DNA including p53 (36%) or partial methylation (28%) of the FLCN/BHD promoter were reported in sporadic renal carcinomas with various histologies.

Mutations have been identified in the mutational hot spot in exon 11 of the FLCN/BHD gene in other tumor types exhibiting microsatellite instability, including colorectal carcinoma (20%), endometrial carcinoma (12%) and gastric carcinoma (16%).

References (open access) :

Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS. Mol Cancer. 2010 Jun 23;9:160.

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. J Med Genet. 2008 Jun;45(6):321-31.

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM. Am J Hum Genet. 2005 Jun;76(6):1023-33.

Focus: Identification of selective inhibitors of cancer stem cells by high-throughput screening. - Focus : Inhibition of Wnt signaling and cancer stem cells - About SALINOMYCIN – A propos de la SALINOMYCINE

Focus: Identification of selective inhibitors of cancer stem cells by high-throughput screening.

Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, SALINOMYCIN, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.

Source: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Gupta Piyush B (, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Cell. 2009 Aug 21;138(4):645-59.
Free paper available at:

La recherche (« screening ») d’agents qui peuvent tuer spécifiquement les cellules souches cancéreuses épithéliales (CSC) n’a pas été possible à cause de la rareté de ces cellules au sein de populations de cellules tumorales et de leur relative instabilité dans la culture. Nous décrivons ici une approche de dépistage des agents ayant une toxicité spécifique des CSC épithéliales. Nous avons implémenté cette méthode et découvert des composés présentant une toxicité sélective pour les CSC mammaires. Un composé, la SALINOMYCINE, réduit la proportion des CSC par >100 fois par rapport au paclitaxel, un médicament couramment utilisé en chimiothérapie du cancer du sein. Le traitement de souris avec la salinomycine inhibe la croissance tumorale in vivo et induit une différenciation accrue des cellules tumorales épithéliales. En outre, les analyses d'expression génique globale montrent que le traitement à la salinomycine résulte dans la perte d'expression de gènes de CSC mammaires précédemment identifiés par des analyses des tissus mammaires isolés directement à partir de patients. Cette étude démontre la capacité d'identifier des agents ayant une toxicité spécifique pour les CSC épithéliales.

Article (en anglais) librement accessible à l’adresse :

Focus : Inhibition of Wnt signaling and cancer stem cells

Source: Inhibition of Wnt signaling and cancer stem cells. Lu Desheng (, Carson Dennis A. Oncotarget. 2011 Aug 21.
Free paper available at:

Article (en anglais) librement disponible à l’adresse:


Salinomycin is used as an antibacterial agent and a coccidiostatic ionophore therapeutic drug. Cocciodosis is a parasitic disease that can strike a variety of animals, but is seen most often in poultry. Because this disease can quickly kill young chicks, most medicated chick food includes salinomycin as an active ingredient. As poultry mature and become resistant to cocciodosis, this element is removed from their food source so that their eggs and meat are not tainted by the drug.

La salinomycine est utilisée comme un agent antibactérien et médicament ionophore coccidiostatique. La cocciodose est une maladie parasitaire qui peut frapper une variété d'animaux, mais elle est enregistrée le plus souvent chez les volailles. Parce que cette maladie peut rapidement tuer les poussins jeunes, la plupart des aliments médicamenteux  pour poulets comprennent de la salinomycine comme ingrédient actif. Lorsque les volailles mûrissent et deviennent résistantes aux cocciodoses, la salinomycine est retirée de leur source de nourriture pour que leurs œufs et la viande ne soient pas entachés par le médicament.

samedi 27 août 2011

Press review (August 27, 2011) – Revue de presse (27 août 2011)

Study shows US women get too many Pap tests
A new study from America's Centers for Disease Control and Prevention (CDC) reveals that many American women are getting too many unnecessary Pap tests, the screening for cervical cancer.
The Independent

Cancer Drug Shortages Getting Worse, FDA Says
Most doctors opt for screening women for cervical cancer more often than guidelines suggest, according to a new study.
By Steven Reinberg. In U.S. News & World Report

Women Who Drink, Smoke Are Less Likely to Stick With Tamoxifen
Women at high risk for breast cancer who smoke and drink are less likely to stick with a drug regimen meant to prevent cancer, a new study finds.
In U.S. News & World Report

Toxicity of aromatase inhibitors may explain lack of overall survival improvement ‎
The toxicities associated with aromatase inhibitors (AIs) may explain the lack of overall survival improvement compared with tamoxifen, according to a study published in the Journal of The National Cancer Institute.
In ecancermedicalscience

Nickel nanoparticles may contribute to lung cancer
All the excitement about nanotechnology comes down to this: Structures of materials at the scale of billionths of a meter take on unusual properties. Technologists often focus on the happier among these newfound capabilities, but new research by an interdisciplinary team of scientists at Brown University finds that nanoparticles of nickel activate a cellular pathway that contributes to cancer in human lung cells.
In R & D Magazine

PARP Inhibitor Promising in a Wide Range of Ovarian Cancers‎
The experimental drug olaparib looks like a promising treatment for a wide range of ovarian cancers, not just those associated with BRCA1 and BRCA2 genetic mutations, according to a new study published online today in Lancet Oncology.
By Fran Lowry. In Medscape

Why Literally Everyone Has Cancer And What This Means For You
I  think  it  is  possible  that  we  might  all  have  cancer. Yes, even you who are reading this column right now. Usually  we  wonder  why  someone  gets  cancer.  This  is  especially  true  when  that  someone  happens  to  be  you,  which  was  the  case  for  me  in  late  2009  when  I  was  diagnosed  with  apparently  aggressive  prostate  cancer  at  age  42. I never thought cancer would happen to me or at least never at such a young age, but there I was out of the blue: a cancer patient.
By Paul Knoepfler. In Science 2.0

Consumer Reports: Quiz reveals facts and myths about skin cancer‎
Some thyroid cancer patients with early disease may be given radioactive iodine unnecessarily, while others with more advanced tumors who should get the treatment don't, a new study suggests.
In Washington Post

Bone drug tied to lower colon cancer risk‎
A new study adds to evidence that bone drugs may play a role in suppressing cancer development, although there is still no proof that taking the medications would stave off malignancies.
By Frederik Joelving. Reuters

Human guinea pigs lend their courage to a golden era of cancer research‎
A single hereditary error in DNA can cause a key anti-cancer gene to switch off, giving a greater risk of developing cancer.
By Sarah Boseley. In The Guardian

Cancers du sang : une forme modifiée d'ecstasy pour détruire efficacement les tumeurs‎
Des chercheurs de l'université britannique de Birmingham ont découvert une forme modifiée de l'ecstasy (MDMA), qui serait 100 fois plus efficace pour détruire les cellules cancéreuses que la drogue elle-même. La trouvaille ouvre alors la voie à une possible application thérapeutique.
Dans MaxiSciences

Cancer du sein : des vaisseaux sanguins qui détruisent les tumeurs
Nouvel espoir dans le traitement des cancers du sein : des chercheurs ont découvert des vaisseaux sanguins capables de favoriser le passage dans les cellules cancéreuses de lymphocytes tueurs. Ces lymphocytes, dont le mode d'action était jusque-là mystérieux, peuvent alors détruire la tumeur plus facilement.
Dans Futura-Sciences

Comment prédire la gravité des cancers de la prostate.‎
Des marqueurs sanguins et urinaires permettent de prédire l'agressivité d'une tumeur, pour adapter les traitements.
Par Sandrine Cabut. Dans Le Figaro

Le cancer expliqué avec des mots simples
« Le Cancer pour les Nuls » ! A première vue, voilà un titre bien léger pour un sujet aussi grave. Les premières pages pourtant, rassurent. Qu’est-ce qu’un cancer ? Comment en réduire le risque ? Quels sont les différents traitements disponibles aujourd’hui ?
Dans Destination Santé

Le vaccin contre le cancer du col de l'utérus protégerait aussi du cancer anal
Un vaccin utilisé pour protéger les jeunes filles contre le cancer du col de l'utérus, dû à des papillomavirus, protège également contre l'infection virale qui peut conduire au développement d'un cancer de l'anus, selon une étude.

Une femme poursuit trois hôpitaux montréalais
Une dame âgée de 55 ans atteinte d'un cancer de l'utérus poursuit trois centres hospitaliers de la grande région de Montréal étant donné les délais de diagnostic et de traitement trop tardifs.