HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model

The influence of growth factors on the proliferative potential of normal and primary breast cancer-derived human breast epithelial cells

In previous studies, we developed serum-free, bovine pituitary extract (BPE)-free culture conditions for the growth of normal and neoplastic rat mammary epithelial cells. The present studies were aimed at determining if these culture methods could be used to study the influence of specific growth factors on the proliferative potential of normal human mammary epithelial (HME) cells and cells derived from human breast cancer (HBC) specimens. Our results indicate that normal HME cells in primary culture express stringent requirements for insulin (IN), epidermal growth factor (EGF), and cholera toxin (CT). Of these factors, EGF is most important, with essentially no proliferation taking place in the absence of this factor. By contrast, when cells are grown in serum-free primary culture in the presence of a full complement of growth factors and then subcultured, growth in secondary culture is not influenced by the removal of individual growth factors. Growth in secondary culture in the absence of EGF is mediated by autocrine factors secreted by the cells. However, there is no evidence for autocrine activity that mediates growth in the absence of IN in secondary cultures. Primary culture of HBC cells in serum-free, BPE-free medium revealed two patterns of growth factor requirements. One set of HBC cells expressed identical requirements for IN and EGF in primary culture as normal cells. Likewise, these cells grew in secondary culture in the absence of either factor. The second set of tumors expressed independence of IN for growth in primary culture. These cells grew to confluence in primary culture in the absence of IN and could be subcultured in this medium. All tumor cells examined expressed a requirement for EGF for primary culture growth, whereas none of the HBC cells examined expressed a significant CT requirement. In many cases, growth in the absence of CT exceeded that observed in its presence. Thus, our culture system allows analysis of the growth factor requirements of HME and HBC cells in primary culture. Our results indicate significant differences between HME and HBC cells in this regard. However, the results of secondary culture experiments indicate that the growth factor milieu from which cells are taken can have a profound effect on the requirements for growth factors in culture.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44196/1/10549_2005_Article_BF01806371.pd

God Krympande Miljö : En undersökning av krympande kommuner och god bebyggd miljö

Detta kandidatarbete undersöker hur kommuner med en krympande befolkning hanterar miljökvalitetsmålet god bebyggd miljö i deras översiktsplaner. Arbetet utfördes genom en kvalitativ textanalys på tre översiktsplaner från Arjeplog, Hofors och Jokkmokk, och försöker besvara tre frågor; Hur beskrivs befolkningsutvecklingen? vad anser kommunen är en god bebyggd miljö? Och vilka konsekvenser har dessa två delar? I till exempel Arjeplog kommun beskrivs befolkningsutvecklingen som en stor utmaning mot kommunens framtida utveckling, och att det är svårare att vända trenden på grund av de relativa höga priserna på villor. I Hofors kommun fokuserar arbetet med en god bebyggd miljö på kollektivtrafik och pendlingsmöjligheter. Jokkmokk kommun presenterar inga tydliga konsekvenser av sina ställningstaganden.  En slutsats som dras är att definitionen av god bebyggd miljö är olika i kommunerna eftersom de behöver utgå från sina egna förutsättningar och problem. En annan slutsats är att det behövs en kompetensutveckling inom social hållbarhet, med anledningen att både god bebyggd miljö och social hållbarhet inkluderar liknande koncept och idéer

God Krympande Miljö : En undersökning av krympande kommuner och god bebyggd miljö

Detta kandidatarbete undersöker hur kommuner med en krympande befolkning hanterar miljökvalitetsmålet god bebyggd miljö i deras översiktsplaner. Arbetet utfördes genom en kvalitativ textanalys på tre översiktsplaner från Arjeplog, Hofors och Jokkmokk, och försöker besvara tre frågor; Hur beskrivs befolkningsutvecklingen? vad anser kommunen är en god bebyggd miljö? Och vilka konsekvenser har dessa två delar? I till exempel Arjeplog kommun beskrivs befolkningsutvecklingen som en stor utmaning mot kommunens framtida utveckling, och att det är svårare att vända trenden på grund av de relativa höga priserna på villor. I Hofors kommun fokuserar arbetet med en god bebyggd miljö på kollektivtrafik och pendlingsmöjligheter. Jokkmokk kommun presenterar inga tydliga konsekvenser av sina ställningstaganden.  En slutsats som dras är att definitionen av god bebyggd miljö är olika i kommunerna eftersom de behöver utgå från sina egna förutsättningar och problem. En annan slutsats är att det behövs en kompetensutveckling inom social hållbarhet, med anledningen att både god bebyggd miljö och social hållbarhet inkluderar liknande koncept och idéer

Egalitarian Values and Sexual Behavior : The Role of Country Level Values in Shaping Individual Level Behaviors in Africa, South America and Asia

The aim of this study is to investigate the relationship between country level egalitarian values (broadly speaking emancipatory values/structural gender equality) and sexual behavior among youth. Methods: Comparative individual level data on sexual activity and condom use were collected from the Global School-based Student Health Survey, resulting in a final sample of 23 countries, analyzed utilizing multilevel logistic regression analysis. Results: Egalitarian values were significantly associated with sexual activity and condom use. Conclusions: Egalitarian values have a relationship with adolescents' sexual activity and condom use, and thus contribute to sexual health and well-being in Africa, South America and Asia