human
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: INTRODUCTION Anterior-gradient 2 ( AGR2 ) is an estrogen-responsive secreted protein . Its upregulation has been well documented in a number of cancers , particularly breast cancer , for which mixed data exist on the prognostic implications of AGR2 expression . Although emerging evidence indicates that AGR2 is associated with poor prognosis , its function and impact on cancer-relevant pathways have not been elucidated in breast cancer . METHODS To investigate the biologic role of AGR2 in breast cancer , AGR2 was transiently knocked down , by using siRNA , in T47 D and ZR-75-1 ( estrogen receptor-alpha ( ER)-positive ) and MDA-MB-231 and SK-BR-3 ( ER-negative ) human breast cancer cell lines . The impact of silencing AGR2 was evaluated in both anchorage-dependent and anchorage-independent growth ( soft agar , spheroid ) assays . Cell-cycle profiles in ER-positive cell lines were determined with BrdU incorporation , and cell death was measured with Annexin V , JC-1 , and F7-26 staining . After transiently silencing AGR2 or stimulating with recombinant AGR2 , modulation of key regulators of growth and survival pathways was assessed with Western blot . Combination studies of AGR2 knockdown with the antiestrogens tamoxifen and fulvestrant were carried out and assessed at the level of anchorage-dependent growth inhibition and target modulation ( cyclin D1 , ER ) . RESULTS AGR2 knockdown inhibited growth in anchorage-dependent and anchorage-independent assays , with a more-pronounced effect in ER-positive cell lines . Cyclin D1 levels and BrdU incorporation were reduced with AGR2 knockdown . Conversely , cyclin D1 was induced with recombinant AGR2 . AGR2 knockdown induced cell death in ZR-75-1 and T47 D cells , and also downregulated survivin and c-Myc . Evidence of AGR2-ER crosstalk was demonstrated by a reduction of ER at the protein level after transiently silencing AGR2 . AGR2 knockdown in combination with fulvestrant or tamoxifen did not preclude the efficacy of the antiestrogens , but enhanced it . In addition , p-Src , implicated in tamoxifen resistance , was downregulated with AGR2 knockdown . CONCLUSIONS Transiently silencing AGR2 in ER-positive breast cancer cell lines inhibited cell growth and cell-cycle progression and induced cell death . Breast cancer drivers ( ER and cyclin D1 ) as well as cancer-signaling nodes ( pSrc , c-Myc , and survivin ) were demonstrated to be downstream of AGR2 . Collectively , the data presented support the utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways .
    OUTPUT:

agent
sustaining proliferative signaling
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: INTRODUCTION Anterior-gradient 2 ( AGR2 ) is an estrogen-responsive secreted protein . Its upregulation has been well documented in a number of cancers , particularly breast cancer , for which mixed data exist on the prognostic implications of AGR2 expression . Although emerging evidence indicates that AGR2 is associated with poor prognosis , its function and impact on cancer-relevant pathways have not been elucidated in breast cancer . METHODS To investigate the biologic role of AGR2 in breast cancer , AGR2 was transiently knocked down , by using siRNA , in T47 D and ZR-75-1 ( estrogen receptor-alpha ( ER)-positive ) and MDA-MB-231 and SK-BR-3 ( ER-negative ) human breast cancer cell lines . The impact of silencing AGR2 was evaluated in both anchorage-dependent and anchorage-independent growth ( soft agar , spheroid ) assays . Cell-cycle profiles in ER-positive cell lines were determined with BrdU incorporation , and cell death was measured with Annexin V , JC-1 , and F7-26 staining . After transiently silencing AGR2 or stimulating with recombinant AGR2 , modulation of key regulators of growth and survival pathways was assessed with Western blot . Combination studies of AGR2 knockdown with the antiestrogens tamoxifen and fulvestrant were carried out and assessed at the level of anchorage-dependent growth inhibition and target modulation ( cyclin D1 , ER ) . RESULTS AGR2 knockdown inhibited growth in anchorage-dependent and anchorage-independent assays , with a more-pronounced effect in ER-positive cell lines . Cyclin D1 levels and BrdU incorporation were reduced with AGR2 knockdown . Conversely , cyclin D1 was induced with recombinant AGR2 . AGR2 knockdown induced cell death in ZR-75-1 and T47 D cells , and also downregulated survivin and c-Myc . Evidence of AGR2-ER crosstalk was demonstrated by a reduction of ER at the protein level after transiently silencing AGR2 . AGR2 knockdown in combination with fulvestrant or tamoxifen did not preclude the efficacy of the antiestrogens , but enhanced it . In addition , p-Src , implicated in tamoxifen resistance , was downregulated with AGR2 knockdown . CONCLUSIONS Transiently silencing AGR2 in ER-positive breast cancer cell lines inhibited cell growth and cell-cycle progression and induced cell death . Breast cancer drivers ( ER and cyclin D1 ) as well as cancer-signaling nodes ( pSrc , c-Myc , and survivin ) were demonstrated to be downstream of AGR2 . Collectively , the data presented support the utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways .
    OUTPUT:
