S6 Breast cancer genetics: clues to tumor biology

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<ul><li><p>S2 Session 2. Biology of breast cancer I Wednesday, 14 March 2007</p><p>The triple negative approach ignores the expression of basal markers,such as basal cytokeratins in the denition of basal-like carcinomas. Inaddition, several morphological studies have demonstrated that very differ-ent breast carcinomas such as some grade 3 invasive ductal carcinomas,medullary carcinomas and metaplastic carcinomas, including carcinosar-comas, expressed basal markers. Regarding the cellular origin of breastcancer, it has been recently suggested that the transformation of differentsubsets of stem and progenitor cells results in the diversity of breast cancerphenotypes, including the expression of basal and luminal markers andoestrogen receptors in breast cancer subtypes. Whether different types ofbreast carcinomas derived either from luminal or myoepithelial cell, or arethe result of luminal cell plasticity or stem/progenitor cell transformation isthe subject of great debate and research.</p><p>Wednesday, 14 March 2007 17.3019.00</p><p>Session 2. Biology of breast cancer I</p><p>S6 Breast cancer genetics: clues to tumor biology</p><p>J. Garber. Dana Farber Cancer Institute, Boston, MA, USA</p><p>The study of genetic susceptibility to breast cancer has focused appro-priately on the identication of individuals at remarkable risk of developingthe disease and identifying strategies for reducing that risk. After BRCA1/2,TP53 and PTEN, additional genes conferring signicant breast cancer riskhave accounted for small percentages of familial cases. Most are membersof DNA repair pathways. The observation that BRCA1-associated breastcancers are negative for ER/PR and HER2 (triple negative) and clusterin microarray analyses with basal-like breast cancers has permitted theinvestigation of the associated DNA repair pathways in these tumors. Cellline data led our group and others to explore the platinum compounds,which induce the double-strand DNA breaks not repaired well by breastcancer cells decient in BRCA1 or BRCA2, in the treatment of these tumors.Work by Ashworth et al. has highlighted the PARP pathway which affectssingle-strand DNA repair defects in BRCA1/2 decient cells: agents target-ing PARP-1 are in clinical trials in Europe and Canada. Other molecularclues from the study of basal-like tumors have provided a number of targetsfor clinical trials ongoing and in development, including EGFR and cKIT.These trials will be reviewed as well.</p><p>S7 Therapeutic implications of the breast tumor intrinsicsubtypes</p><p>C.M. Perou. University of North Carolina at Chapel Hill, LinebergerComprehensive Cancer Center, Chapel Hill, NC, USA</p><p>The use of gene expression assays in clinical medicine is a goal that willonly be realized after validation of the technology and potential classi-cation lists. In order to validate an intrinsic gene list we used a trainingset of 102 tumors to derive a new intrinsic gene list and validated thislist using a true test set of 311 tumors compiled from three independentmicroarray studies. Our analysis showed that common patterns of geneexpression can be identied across different microarray platforms, andthat the breast tumor intrinsic subtypes were identiable within differentdata sets and showed similar patient outcomes. We also showed usingmultivariate analyses, that the intrinsic subtype classication adds valueto the existing repertoire of clinical markers used for breast cancer prog-nostication. Next, we developed a Single Sample Predictor (SSP) for the5 major intrinsic subtypes (Luminal A, Luminal B, Basal-like, HER2+/ERand Normal-like), which is capable of making an assignment on one sampleat a time, and show that the SSP makes prognostic assignments on twoother test data sets not generated by us. In addition to our prognosticintrinsic gene set, a number of other groups have also identied gene setsand methods that predict outcomes in breast cancer patients includingthe 70-gene prole of vant Veer et al., the Genomic Health RecurrenceScore Assay, and a set of genes called the Core Serum Response/CSRdeveloped by Drs. Chang and Brown of Stanford University. Using a testset of 290 new samples from Chang et al. 2005 (PNAS), each sample wasassigned a class for each of these three predictors. Within the Basal-like,Luminal B and HER2+/ER tumor subtypes, great concordance across allpredictors was observed. However, within the Luminal A group, there was</p><p>heterogeneity in predictions, suggesting that further stratication with thislargest group is still needed. These data will be presented in more detailincluding a discussion of the therapeutic implications that is suggested bythe unique expression proles of each group.</p><p>S8 The story of steroid hormone receptors:polymorphisms and endocrine responsiveness</p><p>P. Ciana1, S. Della Torre, A. Stell, A. Biserni, G. Rando, A. Maggi.1Department of Pharmacological Sciences, University of Milan, Milano,Italy</p><p>Sex-hormone receptors are transcription factors involved in the physi-ological regulation of the reproductive function where it may promotetumorigenesis. In reproductive tissues, the physiological activity of estrogenreceptor alpha (ERa) is regulated by a mechanism linking its expressionwith the phases of the female cycle. Receptor expression is maximal atthe proliferative phase in uterus and mammary glands and is promptlydownregulated in the other phases. On target cells, hormone-activated ERainduces proliferation by modulating the transcription of genes encodingkey proteins for cell division (c-myc, c-fos, cyclin D1, D3, E1, E2, andB2) thus accelerating the progression through the G1 restriction pointinto the S phase of the cell cycle. Notwithstanding the importance of themodulation of ERa expression on target tissues, the molecular mechanismunderlying this control is poorly understood. Here we demonstrate that inbreast and endometrial cancer cells the ERa content during the cell cycleis regulated by a mechanism switching off the rate of RNA pol II elongationthrough a block to transcription mapping within intron 1. The DNA cis-acting sequence involved in this regulation is polymorphic in humansand is associated to increased risk of mammary and endometrial cancer.In addition, these polymorphisms are also associated to pathologies ofthe skeletal, cardiovascular and nervous systems. This study reveals anovel mechanism for the regulation of ERa activity and sets a rationale tounderstand the control of cell proliferation by this receptor; in addition, ourdata provides a mechanistic explanation for the association of PvuII andXbaI ERa polymorphysms to disease. Acknowledgments: this work wassupported by the Italian Association for Cancer Research (AIRC) and bythe European Community (Networks of Excellence EMIL, LSH-CT 2004503569 and DIMI LSHB-CT-2005512146).</p><p>S9 Blocking crosstalk between ER and growth factorreceptors to circumvent endocrine resistance</p><p>K. Osborne. Breast Center Baylor College of Medicine Houston, Texas</p><p>Estrogen receptor (ER) stimulates cells via its genomic (nuclear initiatedevents as a transcription factor) and its nongenomic (non-nuclear initiatedeffects) activities. The former is modulated by the milieu of coactivatorsand corepressors and by specic elements in the promoter of targetgenes. ER can also inuence transcription of genes containing AP-1 sitesor SP-1 sites through protein protein interactions with other transcriptionfactors. Nongenomic effects of ER produce rapid activation of growth factorreceptor pathways. In turn, the kinase cascade activated by the growthfactor receptor signaling pathways can functionally activate ER. In modelsystems, the nongenomic or membrane initiated effects of ER becomeimportant when growth factor signaling is abundant, such as in tumors withHER2 overexpression or high levels of EGFR. When both genomic andnongenomic effects of ER are functioning, tamoxifen and other SERMs losetheir antagonist effects and can actually stimulate growth under some cir-cumstances as a mechanism of resistance. Therapies designed to deprivethe cell of ER (aromatase inhibitors) or to downregulate ER (fulvestrant)should be more effective than SERMs in such tumors at least in the shortterm by inactivating both the genomic and nongenomic ER pathways.Blocking the nongenomic effects of ER by inhibiting growth factor signalingwith drugs, such as getinib or trastuzumab, restores tamoxifens antagonistprole and this new treatment strategy using the combination of tamoxifenplus a growth factor inhibitor is now in clinical trials. In experimental models,growth factor pathway inhibitors combined with estrogen deprivation orfulvestrant also delay the onset of acquired resistance to these therapieswhich is accompanied by loss of ER and further upregulation of growth fac-tor signaling. This strategy is also now being tested in clinical trials. Clinicalstudies demonstrating that tumors with high expression of both HER2 andthe ER coactivator AIB1 are highly resistant to tamoxifen support thesepreclinical observations. Finally, combined drug therapy to block signaling</p></li></ul>

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