Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors

BackgroundBRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Methodology Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Results Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFβ2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004). SignificanceBRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFβ pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Induction of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) can occur as the result of embryonic pathway signaling. Activation of Hedgehog (Hh), Wnt, Notch, or transforming growth factor-β leads to the upregulation of a group of transcriptional factors that drive EMT. This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. CSCs and the EMT process are currently being investigated for the role they play in driving metastatic tumor formation in breast cancer. Both are very closely associated with embryonic signaling pathways that stimulate self-renewal properties of CSCs and EMT-inducing transcription factors. Understanding these mechanisms and embryonic signaling pathways may lead to new opportunities for developing therapeutic agents to help prevent metastasis in breast cancer. In this review, we examine embryonic signaling pathways, CSCs, and factors affecting EMT

New insights into the aetiology of scrotal cancer, a nationwide case-control study in the Netherlands.

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Evaluation of cognitive, behavioural and relaxation treatments for chronic low back pain

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Possible incorporation of free N7-platinated guanines in DNA by DNA polymerases, relevance for the cisplatin mechanism of action

Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used anticancer drugs. The main cellular target of cisplatin is DNA, where the platinum atom is able to form covalent bonds with the N7 of purines. It is commonly accepted that there is a direct attack of cisplatin to DNA. But it should be noted that, inside cells, free purine bases, which can react with cisplatin, are also available. Free bases have many functional roles, not least the constitution of building blocks for the synthesis of new DNA and RNA molecules. For this reason, under physiological conditions, the erroneous insertion of platinated bases in the synthesized nucleic acids could compete with direct DNA/RNA platination. Moreover, due to the lower sterical hindrance offered by single nucleobases with respect to nucleic acids, platination is expected to be even easier for free purines with respect to DNA and RNA. We have recently shown, for the first time, that platinated DNA can be formed in vitro by Taq DNA polymerase promoted incorporation of platinated purines. Cytotoxicity tests with [Pt(dien)(N7-G)], dien = diethylenetriamine, G = 5’-dGTP, 5’-dGDP, 5’-GMP, 5’-dGMP, GUO, dGUO, complexes on HeLa cancer cells support this hypothesis being the relative cytotoxicity of [Pt(dien)(N7-G)] derivatives clearly related to their bioavailability. In vivo platination of free purines before their incorporation in nucleic acids opens therefore new perspectives in platinum based antitumour drugs, for both action mechanism better understanding and new molecular design

Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates.

The breast epithelium has two major compartments, luminal and basal cells, that are established and maintained by poorly understood mechanisms. The p53 homolog, p63, is required for the formation of mammary buds, but its function in the breast after birth is unknown. We show that in primary human breast epithelial cells, maintenance of basal cell characteristics depends on continued expression of the p63 isoform, DeltaNp63, which is expressed in the basal compartment. Forced expression of DeltaNp63 in purified luminal cells confers a basal phenotype. Notch signaling downmodulates DeltaNp63 expression and mimics DeltaNp63 depletion, whereas forced expression of DeltaNp63 partially counteracts the effects of Notch. Consistent with Notch activation specifying luminal cell fate in the mammary gland, Notch signaling activity is specifically detected in mice at sites of pubertal ductal morphogenesis where luminal cell fate is determined. Basal cells in which Notch signaling is active show decreased p63 expression. Both constitutive expression of DeltaNp63 and ablation of Notch signaling are incompatible with luminal cell fate. Thus, the balance between basal and luminal cell compartments of the breast is regulated by antagonistic functions of DeltaNp63 and Notch.Cell Death and Differentiation advance online publication, 9 April 2010; doi:10.1038/cdd.2010.37