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Tag Archives: breast cancer

Friday Science Review: May 7, 2010

Amazing!  Three Nature papers this week…

Cracking the Code: The human body is much more complex than the 20,000 or so genes that are encoded in our DNA.  This multiplicity of genetic messages is enhanced by alternative gene splicing, a process where different segments of DNA exons are spliced together to create a different gene message.  It is possible to create hundreds of new messages from a single gene.  The so called “splicing code” or rules that determines how and where a particular part of a gene is spliced with another segment was deciphered by researchers at the University of Toronto.  They can now accurately predict how genetic messages are rearranged on a large scale.  Hundreds of different RNA features are taken into account including certain factors in specific tissues to give rise to tissue specific expression.  This is an amazing discovery by Drs. Brendan Frey and Benjamin Blencowe that garnered the cover story in this week’s Nature journal.

Stem Cells on Hormones: The ovarian hormone, progesterone, stimulates breast stem cells as its levels peak during the natural reproductive cycle.  Researchers observed up to a 14-fold expansion of breast stem cells at peak progesterone levels in a mouse model.  This is the first evidence of a direct link between hormones and breast stem cells.  Since cancers are thought to initiate from stem cells, if there are other oncogenic factors pushing the system this may be a critical point that ultimately drives the start of a cancer.  There are implications of this study to further understanding how reproductive history is a strong risk factor for breast cancer and may lead to therapeutic intervention.  The research team at Princess Margaret Hospital, University Health Network was led by Dr. Rama Khokha and describes their work in Nature.

Reversing HER2 Breast Cancer: Through genomic studies of HER2 positive breast cancer, it was noted that the 14-3-3sigma gene was frequently missing.  After several years of hard work focusing on this gene, researchers have demonstrated that the 14-3-3sigma gene does indeed play a specific role in the development and function of breast epithelial tissue.  In the absence of 14-3-3sigma, the normally organized and polarized sheets of epithelial cells clump together and lose polarity.  It is this loss of organization without 14-3-3sigma that likely contributes to breast cancer progression.  From a therapeutic standpoint, the reintroduction of 14-3-3sigma into HER2 positive breast cancer cells resulted in the restoration of cell polarity and opens a window for further studies as a pathway to target.  Dr. William Muller (my former mentor) and his team at McGill University describe their research in the early edition of Genes and Development.

Bionic Muscle: Artificial proteins were assembled together in a fashion that mimics the molecular spring structure of a muscle protein called Titin, which is a very large protein that gives muscle tissue its unique properties of strength, extensibility and resilience.  This is why muscle has superior elasticity.  The biomaterial looks like a string of beads and although it exhibits only some of the mechanical characteristics of muscle tissue, its structure can be adjusted to provide specific properties of different types of muscle.  There are obvious future applications of this technology in regenerative medicine and tissue engineering.  Drs. Hongbin Li and John Gosline at the University of British Columbia present their work in this week’s Nature journal.

Friday Science Review: October 9, 2009

Breast cancer, genomics and two cover stories in prestigious journals…

Cancer Evolution and Progression:  Scientists at the BC Cancer Agency have sequenced and compared the entire cancer genome of a metastatic tumour versus the primary breast tumour that originated nine years earlier.  They used next generation DNA sequencing technology to reveal 32 mutations in the metastatic cancer but surprisingly only five of these were present in the original tumour.  Six mutations were present at lower frequencies in the primary tumour, 19 were not detected and 2 were undetermined.  These differences may provide clues about how cancer becomes resistant to therapy or how a tumour switches to aggressive metastasis that spreads to other sites in the body.  The study demonstrated that cancers evolve and that there may be significant heterogeneity within the tumours.  These findings emphasize the importance of ongoing research efforts to sequence all cancer genomes and buttress arguments in favour of personalized medicine.

The study was lead by Dr. Samuel Aparicio at the BC Cancer Agency and appears as the cover story in the latest edition of Nature.

Honey, I shrunk the lab: The “lab-on-a-chip” concept has been in use for a number of years but Dr. Aaron Wheeler’s Microfluidics Laboratory at the University of Toronto has designed a new module for use in breast cancer detection and care.  The hand-held sized device can extract and quantify estrogen in a very small sample size – as little as a 1 microliter sample of tissue or blood – by using electrical charges to move liquids around in a precise manner over a microchip.  Current methods require a much larger sample, about the size of a penny, which is often impractical to obtain.  Since elevated estrogen levels are associated with breast cancer risk and pathogenesis, this new device could be used at point-of-care to screen at-risk patients or to monitor therapies and provide results within minutes instead of days.

Dr. Wheeler collaborated with Dr. Robert Casper (University of Toronto and Samuel Lunenfeld Research Institute) on this project, which garnered the inaugural cover story in the new journal, Science Translational Medicine.

Genome Map Upgrade: Researchers have generated a comprehensive structural map of the human genome in identifying and marking regions that are duplicated or deleted, the so-called copy number variation (CNV).  Genetic variation is what makes us different and certain areas of the genome reflect these differences whereas other genetic regions show very little variation and are likely essential function genes.  It also provides important clues to understanding evolution and provides the foundation for future research in developing personalized medicine.   The international study was co-lead by Dr. Stephen Scherer at The Centre for Applied Genomics (Hospital for Sick Children, Toronto) and provides the following comments:

“The scale of this current project is 100 times the scale of all others.”

“Previous work in this field would be like a paper fold-up map; this advancement is like a GPS that takes you where you need to go. It allows you to navigate the landscape of the genome, from its peaks where there is vast genetic variation, to its valleys devoid of it.”

“Variation is indeed the spice of life and we now know that nature buffers this variation by using CNVs. We are harnessing this knowledge to fight disease.”

Dr. Scherer is also involved in maintaining the Database of Genomic Variants, which provides researchers around the world access to a curated catalog of CNVs.  Details of the research report appear in the advanced on-line edition of Nature.

Congratulations to McGill University alumni Jack Szostak and Willard Boyle for winning the 2009 Nobel Prize in their respective disciplines.

Dr. Jack Szostak started at McGill when he was 15 years old and graduated in 1972, specializing in cell biology.  This was the start of a brilliant research career where he co-discovered how telomeres and telomerase protects chromosomes from losing genetic material during cell division.  He shares the 2009 Nobel Prize for Medicine.

Dr. Willard Boyle completed his BSc (1947), MSc (1948) and PhD (1950) from McGill.   He shares the Nobel Prize for Physics for the 1969 co-invention of the charged-couple device (CCD) that is used in today’s digital photography technology.

Trends Update — Comparative Effectiveness and Personalized Medicine: Is Canada Ahead of the U.S. In the Use of HER2 Testing for Personalized Breast Cancer Treatment?

B&W_DNA_sequenceFor the 20%-30% of breast cancer patients with tumors that overexpress HER2, treatment with Herceptin (an antibody drug from GenetechRoche) is highly effective.  That’s why this article in the journal Cancer is so shocking.  The authors gathered data from a variety of published sources and estimate that:

“up to 66% of eligible patients had no documentation of testing in claims records, up to 20% of patients receiving trastuzumab were not tested or had no documentation of a positive test, and 20% of HER2 results may be incorrect.”

I asked a friend, who is a genetic counsellor in Toronto, if she thought the gaps here were as bad.  She said no, and that she would be extremely surprised not to see a HER2 result in a patient’s file.

Of course it’s not valid to draw conclusions about national health care from a comparison of the Cancer study to my anecdote.  Among other reasons, the authors admit their data is flawed and dated, and my friend works at one of Canada’s top teaching hospitals.  Nevertheless, the possibility that many U.S. patients could be falling through the cracks is extremely disturbing.

If clinicians can’t adopt and maintain near-universal use of a personalized medicine approach like HER2-Herceptin with recognized and measurable benefits, the future of pharmacogenomics is in some big trouble and we will never generate truly useful comparative effectiveness data.

H/T @FiercePharma.

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Friday Science Review: August 21, 2009

This week… cancers, brains, and fruit flies.

Combinatorial therapy to fight melanoma: Malignant melanomas are aggressive cancers that are highly resistant to chemotherapy, possibly due to high levels of Bcl-2 family anti-cell death  proteins.  Although the small molecule inhibitor, ABT-737, is effective against Bcl-2 family proteins in other cancers, it is not very effective in melanoma cases.  The reason may be due to overexpression of another protein, Mcl-1, which confers resistance to ABT-737.  When  Dr. Victor Tron’s group at Queen’s University combined ABT-737 treatment with inhibitions of Mcl-1 by way of siRNA knockdown, the cancer cells lost their resistance and underwent cell death.  These findings, appearing this week in PloS One , suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma.

Understanding Stat3 in Breast Cancer: Elevated Stat3 levels in breast cancer patients often correlate with poor clinical outcome.  To understand how Stat3 may influence cancer progression, a Stat3 knockout mouse was combined with a mouse expressing the mutant form of the breast cancer gene, ErbB2, and predisposed to develop breast tumours.  What the researchers at McGill University found was that without Stat3, breast cancer still developed but the malignancy of the mammary tumours decreased significantly with fewer animals having metastatic lesions in the lung.  Genetic profiling of the tumours showed that without Stat3, angiogenic and inflammatory responses, which often play an important role in the metastatic process, were blunted.  Remember, last week I noted an article on Par6 and TGFb in breast cancer metastasis.

This recent study, hot off the press in Cancer Research, was led by Dr. William Muller, one the early pioneers in using transgenic mouse technology.

Gene expression differences in suicide brains: This is the first study to perform global gene expression analysis on the brains of suicide cases to try to broaden the scope of suicide research to other neurotransmitter systems.  The serotonergic system is well studied as the primary area of the brain involved in suicides but there are likely other contributing factors.  Dr. Turecki’s research team at McGill University performed microarray expression studies on a number of brain tissue samples from the cortical and subcortical regions to identify potentially new molecular pathways involved in depression and suicide.  Their results revealed a number of alterations including genes involved in synaptic neurotransmission, namely upregulation of glutamatergic (excitatory) and GABAergic (inhibitory) related genes in suicide brains.  This report in PLoS One should open the research field into exploring alternate treatment methods and better understanding the development of suicide and depression.

Male hormone discovery: A new male-specific pheromone was identified on fruit flies.  When the researchers transferred some of the compound onto female fruit flies, the male flies were suddenly uninterested.  How did they identify this pheromone?  They exposed a fruit fly to a laser in a MALDI-type mass spectrometer instrument where ions are ejected into the instrument and analyzed.  Some previously unidentified compounds were discovered including this hormone.  The research was conducted at the University of Toronto Mississauga by Joel Levine and Jocelyn Millar and appears in this week’s Current Biology.

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Friday Science Review: Screening Edition

Early Screening for Breast Cancer Risk:

Pink RibbonA group of Canadian researchers showed that using MRI (magnetic resonance imaging, not the Ministry of Research and Innovation) to estimate breast tissue density may provide information on breast cancer risk comparable to measuring density by mammography.  Because MRI does not use radiation, earlier screening by MRI would avoid the culumative radiation exposure problems of mammography, although the effect, if any, on clinical outcomes remains unknown.  The authors’ interpretation:

Per cent breast water [(density)] was greatest during the ages when women are most susceptible to breast carcinogens, and was associated with weight, height, and mother’s breast-tissue characteristics, and with serum concentrations of growth hormone: a breast mitogen that also mediates postnatal somatic growth. Mammographic density in middle age might partly be the result of genetic factors that affect growth and development in early life.

The study appears in the advanced online publication section of The Lancet Oncology.

Screening for Plant Genes:

ArabidopsisAfter many years of searching, Arabidopsis receptors for abscisic acid (ABA) were identified.  ABA helps plants survive drought and other stresses; and as it turns out, there are 13 receptors for it, with the redundancy foiling previous screening techniques.  This week, a novel screen developed in a collaboration among scientists at UC Riverside, the University of Ontario Institute of Technology, University of Toronto, Universidad Politécnica de Valencia in Spain and other institutions in the U.S. and Spain identified one of the family members and used that one to find its relatives.  The PYR/PYL proteins are a family of START receptors that the authors place “at the apex of a negative regulatory pathway that controls ABA signaling by inhibiting PP2Cs.”  Their work was published this week in Science’s advance publication, Science Express. 

Put this together with the reports in Nature this week showing targeted insertions in the plant genome, and you have  a powerful set of tools to start engineering drought and stress resistant crops.  The targeted plant vectors use a zinc-finger nuclease, designed from a public database created by Daniel Voytas at University of Minnesota, J. Keith Joung at Mass Gen and their colleagues.

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Trends Update — Personalized Medicine: Clinical Data on Personalized Cancer Treatment

A study presented at the American Association for Cancer Research meeting this week showed benefits to patients from using molecular profiling to customize chemotherapy regimens.

The pilot study, with Daniel Von Hoff, M.D. as the senior investigator, used immunohistochemistry and microarray profiling to select treatment regimens for 66 patients who had ovarian, colorectal, breast and other cancers.   The data compared progression-free survival and tumor size after the patients moved to a new treatment regimen with the same patients’ progression before molecular profiling.  Forty percent of patients in the trial survived at least 15 months compared to 20 percent of the control population.

A story in Forbes notes personalized cancer treatment data in a colon cancer study and two glioblastoma studies that were also presented at the AACR meeting.
 

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Trends in 2009: Personalized Medicine and Cancer Update

The Boston Globe reported this week on current trends in genetic testing of tumors:

  • Massachusetts General Hospital will be adding $2,000 per patient worth of genetic testing as part of its standard of care for cancer.
  • Dana-Farber tests selected patients, including patients with certain melanomas, where doctors know those malignancies can carry abnormalities that are susceptible to certain drugs.
  • Memorial Sloan-Kettering Cancer Center in New York, will start screening most patients with lung cancer within weeks.

This week has seen some scientific developments reported in tumor screening as well:

  • A study in PNAS reports on an analysis of genome-wide expression and copy-number data in endometrial cancers and finds a couple of prognostically-relevant results.
  • A study in the Journal of Clinical Oncology reports on the use of a 50 gene array to successfully identify four breast cancer tumor types that have been previously defined: luminal A, luminal B, HER2-enriched and basal-like.

We’ll see if the accumulation of data is sufficient to make a case for insurance coverage.

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Friday Science Review: February 6, 2009

Friday Science Review: January 30, 2009

Interesting science developments in and from Canada this week:

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