13.03.2015

Understanding drug resistance in breast cancer with mathematical oncology

Estrogens are responsible for the survival and proliferation of tumor cells in 70% of all breast cancer cases.
Receptor proteins that bind estrogens regulate the expression of genes that are necessary to the survival and proliferation of certain types of mammary cells. Didier Picard, professor at the Department of Cell Biology of the Faculty of Sciences of UNIGE, studies the functioning of ER? and its involvement in the resistance to tamoxifen. The biologists tested various compounds in vitro on mammary cancer cells having become refractory to tamoxifen. The pharmacological equivalents of these compounds are currently being used in various human clinical trials. Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality.
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The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. The new study in Nature tracks the evolution of a breast cancer, a diagnosis that becomes more common with age. Nature is now reporting the most thorough study of evolution in a single patient’s breast cancer. The ability to look in detail at cancer genes raises the prospect of eventually understanding the cause of the many diseases we call cancer. Understanding these early and late mutations could shed light on the origin and spread of cancer. High-speed sequencing could eventually help doctors select treatments based on the genetics of the cells in the tumor, and Aparicio says his team has already begun tracking patient’s genes. Making treatment decisions could be complicated, however, as even the original tumor showed genetic weirdness that is not found in healthy tissue.
Sequencing DNA relies upon matching pairs of components that have specific preferences for partners. Scientists have wanted to understand the changing genetics of cancer for decades, but this study was only possible due to phenomenal advances in sequencing speed that are meanwhile causing the cost to drop, some say, faster than the price of computers. Ultra-speed “synthesis DNA sequencing” relies on DNA’s ladder-shaped, double-stranded structure.
Technicians start synthesis sequencing by splitting the DNA ladder lengthwise and anchoring millions of short strands to a sample plate.
Synthesis sequencing is just catching on, and the current study looked at one tumor, from one patient. However, one mutation that already seems portentous is HAUS3, which causes defects in proteins that organize the chromosomes as they undergo the delicate process of uncoiling, duplicating, and recoiling during cell division, Aparicio says. The secondary cancer, called a metastasis, is more likely to cause death than the primary tumor. As an early look into the tangled genomics of cancer, the study is a good first step, says Michael Gould, an oncologist at the University of Wisconsin-Madison School of Medicine and Public Health. However, Gould adds that compared to a previous study of the blood cancer leukemia, the British Columbia study also found more genetic change over time. As Aparicio says, the treatment goal of this type of genomic analysis is already beginning, as researchers try to correlate different genetics with treatment outcomes. BibliographyMutational evolution in a lobular breast tumour profiled at single nucleotide resolution, Sohrab P.
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Bovine milk, which is known to contain naturally occurring estrogens, was so far assumed to play a negative role in human reproductive health.
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Reserve Bank of India (RBI) has provided the framework under which banks can have their own board approved policy for One Time Settlement (OTS) or compromise settlements. The most frequently used treatment to fight this variety of tumors relies on anti-estrogens such as tamoxifen. When breast cancer cells possess estrogen receptors of the ? type (ER?), that is 70% of the time, these receptors constitute a motor of cancerous growth.
Diverse protein complexes and cofactors are also at work to activate ER? or to regulate these genes’, explains Marcela Bennesch, first author of the study. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease.
Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway.
Tumor cells don’t do the work of a healthy cell, but they are awfully good at making sloppy copies of themselves. The sequencing machine then introduces new bases and watches as they complete the anchored strands. To understand which mutations are most dangerous, “one really has to … look at multiple cancers,” Aparicio says.
However, nearly a third of the patients develop a resistance to this type of therapy after a few years. Treatments with anti-estrogens such as tamoxifen block malignant cell growth precisely by inhibiting the activity of ER?. However, the binding of this protein to ER? was, by itself, insufficient to activate the receptor. Furthermore, these drugs restore tamoxifen sensitivity to the malignant cells’, says Didier Picard.
As for treatments blocking HDAC, they are currently being tested in several clinical trials targeting this type of tumor.
Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity.
Removed from the normal restraints and error-checking that keep healthy cells honest, cancer cells can change over time as they evolve to fight the immune system and cancer drugs. But now, techniques for hyperspeed DNA sequencing are starting to produce libraries of genetic data, raising the hope of unraveling the varying genetics of cancer. In the Aparicio study, the tumor cells nine years after diagnosis showed 32 significant mutations, only five of which were common in the original tumor.
In a study published in the journal Nucleic Acids Research, biologists from the University of Geneva (UNIGE), Switzerland, reveal how tumor cells become refractory to the drug. However, the cancer eventually becomes refractory to these hormonal therapies in more than one third of the patients.


The biologists then looked for the other cellular factors involved and discovered seven additional molecules. The same applies to the chaperone protein Hsp90, which, besides its usual roles of assistance to other proteins, participates in the assembly of factors involved in the mechanism of resistance to tamoxifen. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity. They succeeded in identifying eight factors involved in the process of resistance to the treatment. Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation.
Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations.
Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen.
Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. Paclitaxelinduced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells.
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells.
FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1.
Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells.
Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. FoxM1 promotes ?-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. ATMand p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance. The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. ER?1 represses FOXM1 expression through targeting ER? to control cell proliferation in breast cancer.
FOXO3a represses VEGF expression through FOXM1-dependent and-independent mechanisms in breast cancer.



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