Abstract:
BACKGROUND:CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells. METHODS:We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach. RESULTS:ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden. CONCLUSIONS:Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Balcioglu O,Heinz RE,Freeman DW,Gates BL,Hagos BM,Booker E,Mirzaei Mehrabad E,Diesen HT,Bhakta K,Ranganathan S,Kachi M,Leblanc M,Gray PC,Spike BTdoi
10.1186/s13058-020-01361-zsubject
Has Abstractpub_date
2020-11-13 00:00:00pages
125issue
1eissn
1465-5411issn
1465-542Xpii
10.1186/s13058-020-01361-zjournal_volume
22pub_type
杂志文章abstract::This cross-sectional investigation in Hawaii explored the relation between soy foods and mammographic characteristics using two food frequency questionnaires and a computer-assisted density assessment method. Japanese and Chinese women reported significantly greater soy food intake than Caucasian women. Whereas soy in...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr285
更新日期:2001-01-01 00:00:00
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journal_title:Breast cancer research : BCR
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abstract:BACKGROUND:The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1512
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissu...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1603
更新日期:2006-01-01 00:00:00
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journal_title:Breast cancer research : BCR
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0656-2
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr603
更新日期:2003-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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pub_type: 杂志文章,多中心研究
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更新日期:2008-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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journal_title:Breast cancer research : BCR
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,meta分析
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更新日期:2007-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
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更新日期:2007-01-01 00:00:00
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更新日期:2009-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,多中心研究
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:Breast cancer research : BCR
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更新日期:2004-01-01 00:00:00
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更新日期:2010-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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更新日期:2015-04-25 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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更新日期:2005-01-01 00:00:00