Breaking News
March 19, 2019 - Study of young athletes suggests snoring and sleep apnea are linked to sudden cardiac death
March 19, 2019 - Did Your Doctor ‘Ghost’ You? An Employment Contract May Be To Blame
March 19, 2019 - Food pantry clients more likely to make healthy choices when meal kits and recipe tastings are available
March 19, 2019 - Mental health problems among children increasing
March 19, 2019 - New ISO standard helps evaluate and manage impact of environmental damage
March 19, 2019 - CardioMEMS heart failure sensor reliably safe, effectively reduces hospitalizations
March 19, 2019 - Researchers report promising results of potential reversal agent
March 19, 2019 - Scientists identify brain circuit responsible for cocaine-seeking behavior during relapse
March 19, 2019 - First African-American Neuroscience Research Initiative launched to close the gap in health disparities
March 19, 2019 - Bimekizumab Demonstrated Long-Term Maintenance of Complete or Almost Complete Skin Disease Resolution for Psoriasis Patients in BE ABLE 2 Extension Study
March 19, 2019 - Attitudes about health affect how older adults engage with negative health news
March 19, 2019 - Huron Digital Pathology to unveil new ‘Scan Index Search’ platform at USCAP 2019
March 19, 2019 - Frequent intake of sugary drinks tied to greater risk of premature death
March 19, 2019 - Bruker showcases new analytical systems and applied market solutions at Pittcon 2019
March 19, 2019 - Framingham cardiovascular risk prediction model from the 1990s still gives the best results
March 19, 2019 - New article focuses on integrative health, value-based medicine, and whole systems research
March 19, 2019 - Foamix Announces FDA Acceptance of New Drug Application for FMX101 Minocycline Foam for the Treatment of Moderate-to-Severe Acne
March 19, 2019 - National survey of emergency dept management of self-harm highlights successes, room for improvement
March 19, 2019 - Scientists reverse alcohol-seeking behavior in rats with flip of a switch
March 19, 2019 - Researchers hope blood test that accurately diagnoses fibromyalgia could be available within five years
March 19, 2019 - New Planmeca ProScanner 2.0 offers fast and dependable intraoral imaging
March 19, 2019 - A new option for reducing LDL cholesterol in patients at high risk for heart attack, stroke
March 19, 2019 - Common medications to treat heartburn linked to increased risks for kidney failure
March 19, 2019 - Current HBV genome sequences help deduce ancient human population movements into Australia
March 19, 2019 - Pure omega-3 prescription drug significantly reduces the occurrence of ischemic events
March 19, 2019 - Researchers use big data to gain better understanding of hepatitis E virus
March 19, 2019 - Use of synthetic psychedelic linked to improvements in depression and anxiety
March 19, 2019 - GARP protein can be a potential target for immunotherapy against colorectal cancer
March 19, 2019 - Knee Pain Not Tied to Activity Levels in Knee Osteoarthritis
March 19, 2019 - Study shows benefits of delayed cord clamping in healthy babies
March 19, 2019 - Pharmacists can undertake overall clinical responsibility for patients, shows study
March 19, 2019 - A cell’s “self-destruct” function could yield new therapies
March 19, 2019 - Latest advances and perspectives of all AI types used in pharmaceutical R&D
March 19, 2019 - Prophylactic cranial irradiation used as standard approach for patients with NSCLC
March 19, 2019 - Sugar-sweetened beverages may be linked with increased risk of cardiovascular mortality
March 19, 2019 - AHA News: Black Woman in Their 50s Face Especially High Stroke Risk
March 19, 2019 - Secrets of early life revealed from less than half a teaspoon of blood
March 19, 2019 - Immune cells engineered to tattle on suspicious cells in the body
March 19, 2019 - Heart attack patients who are taken to heart care centres directly survive longer
March 19, 2019 - IVF babies have increased in birthweight over the past 25 years, study reveals
March 19, 2019 - Study highlights the need for psychiatric care to be integrated into cancer treatment
March 19, 2019 - Testosterone treatment lowers recurrence rates in low-risk prostate cancer patients
March 19, 2019 - Caterpillars could hold the secret to new treatment for Osteoarthritis
March 19, 2019 - Parkinson’s treatment delivers a power-up to brain cell ‘batteries’
March 19, 2019 - Stanford launches new Institute for Human-Centered Artificial Intelligence
March 19, 2019 - Wireless earphones may cause cancer
March 18, 2019 - ACC/AHA guideline for prevention of cardiovascular disease released
March 18, 2019 - UTA nursing professor receives $6.575 million to attack musculoskeletal diseases
March 18, 2019 - Gene medication shows promise to treat spinal cord injuries
March 18, 2019 - First Human Study of “Robotic” RaniPill™ Capsule to Replace Injections Announced by Rani Therapeutics
March 18, 2019 - Food Allergy Testing: MedlinePlus Lab Test Information
March 18, 2019 - Altered brain activity patterns of Parkinson’s captured in mice
March 18, 2019 - Apple Heart Study demonstrates ability of wearable technology to detect atrial fibrillation | News Center
March 18, 2019 - Cardiovascular benefits of diabetes drug extend across a wide spectrum of patients, shows study
March 18, 2019 - Novel cardiac pump shows superior outcomes in patients with advanced heart failure
March 18, 2019 - U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis
March 18, 2019 - Living like a caveman won’t make you thin—but it might make you healthy
March 18, 2019 - Modified immune cells issue alert when detecting cancer in mice | News Center
March 18, 2019 - Dementia caregivers design robots for alleviating stress and increasing joyful moments
March 18, 2019 - VR technology could help improve balance in humans
March 18, 2019 - Study demonstrates effective way to slow progression of cerebrovascular disease in older adults
March 18, 2019 - Premature babies also have protective anti-viral antibodies
March 18, 2019 - Painkillers taken by pregnant mothers unlikely to cause asthma in the child
March 18, 2019 - Fibromyalgia can be reliably detected in blood samples
March 18, 2019 - Marijuana use has dropped among most teens after legalization
March 18, 2019 - Legacy Pharmaceutical Packaging, LLC Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25mg, 50mg, And 100mg Due to The Detection of Trace Amounts Of N-Nitroso N-Methyl 4-Amino Butyric Acid (NMBA) Impurity Found in The Active Pharmaceutical Ingredient (API)
March 18, 2019 - Researchers identify early home and family factors that contribute to obesity
March 18, 2019 - Fate and festivity: Match Day 2019
March 18, 2019 - Study finds TAVR to be as good as open-heart surgery for patients at low surgical risk
March 18, 2019 - EU-funded project is developing new tools for diagnosing cancer
March 18, 2019 - Gluten, lactose, food dyes in pills could be causing side effects finds study
March 18, 2019 - Taking painkillers during pregnancy is not responsible for asthma risk in children, study shows
March 18, 2019 - Prediagnosis Psychiatric Care Linked to Worse Cancer Mortality
March 18, 2019 - Paris hospital halts stool study after donor deluge
March 18, 2019 - Partial oral antibiotic therapy shows efficacy and safety in patients with infectious endocarditis
March 18, 2019 - Olympus improves access to science education through BioBus collaboration
March 18, 2019 - Depression screening does not improve quality of life in heart attack patients
March 18, 2019 - Echocardiography may aid in patient selection for TMVR
March 18, 2019 - Are ‘Inactive’ Ingredients in Your Drugs Really So Harmless?
March 18, 2019 - Wearable technology can safely identify atrial fibrillation
Loss of specific protein makes breast cancers more aggressive, resistant to chemotherapy

Loss of specific protein makes breast cancers more aggressive, resistant to chemotherapy

image_pdfDownload PDFimage_print

Researchers in Italy have discovered how specific versions of a protein called Numb protect the key tumor suppressor p53 from destruction. The study, which will be published December 21 in the Journal of Cell Biology, suggests that the loss of these particular Numb proteins makes breast cancers more aggressive and resistant to chemotherapy, but points the way toward new therapeutic approaches that could improve patient outcome by preserving p53 levels.

Cells produce several alternative isoforms of Numb by differentially processing, or splicing, the mRNA encoding Numb to include or exclude specific regions of the protein. How this alternative splicing affects Numb’s various functions remains unclear.

In mammary gland stem cells, for example, Numb binds and inhibits an enzyme called Mdm2, preventing it from targeting p53 for degradation. Numb therefore stabilizes p53 and allows this tumor suppressor protein to limit stem cell proliferation. If the stem cells lose Numb, however, p53 levels plunge and the cells proliferate uncontrollably, leading to the emergence of cancer stem cells that drive the growth of breast tumors. Cancer cells that lack p53 are also more resistant to chemotherapy drugs that kill cells by damaging their DNA.

A team of researchers based in Milan set out to identify how Numb binds to Mdm2. The team was led by Pier Paolo Di Fiore of the FIRC Institute for Molecular Oncology (IFOM), the European Institute of Oncology (EIO), and The University of Milan, as well as Salvatore Pece of EIO and The University of Milan and Marina Mapelli of EIO.

The researchers found that a small region of Numb–comprising just 11 amino acids–is responsible for binding and inhibiting Mdm2. This region is present in Numb isoforms 1 and 2 but excluded from isoforms 3 and 4. Accordingly, depleting Numb-1 and -2 from breast cancer cells reduced the levels of p53, whereas depleting Numb-3 and -4 had no effect.

The researchers then compared tumor cells isolated from multiple different breast cancer patients and found that cells expressing lower amounts of Numb-1 and -2 were more resistant to the chemotherapy agent cisplatin. Treating these cells with an Mdm2 inhibitor boosted p53 levels and increased the cells’ sensitivity to cisplatin.

“We reasoned that breast cancers displaying reduced levels of Numb-1 and -2, being resistant to genotoxic agents, might also display poorer disease outcome,” explains Pece.

The team therefore analyzed the case history of 890 breast cancer patients and found that low Numb-1 and -2 levels correlated with an increased risk of aggressive, metastatic disease, particularly for the luminal subtype of breast cancers, which tend to retain a normal, functional copy of the p53 gene.

“Our results show how Numb splicing specifically impacts the regulation of p53 and breast cancer prognosis,” Mapelli says.

“We hope that it will be possible to exploit the knowledge of the molecular basis of the Numb-Mdm2 interaction in the rational design of molecules that can mimic the crucial region in Numb and inhibit Mdm2 to relieve p53 dysfunction in Numb-defective breast cancers,” Di Fiore says.

Tagged with:

About author

Related Articles