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Breast Cancer Progression and Metastasis: Discovery of Novel Genes and Their Functional Study
Başlık:
Breast Cancer Progression and Metastasis: Discovery of Novel Genes and Their Functional Study
Yazar:
Liu, Yin, author.
ISBN:
9780355986990
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (170 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Kounosuke Watabe Committee members: Hui-Wen Lo; Linda Metheny-Barlow; Lance D. Miller; Pierre-Alexander Vidi.
Özet:
Breast cancer is one of major public health problem worldwide. However, the underlying molecular mechanism of breast cancer progression and metastasis is not well understood. Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer which could progress to or recur as invasive breast cancer. To identify the novel regulators of DCIS progression, we performed gene expression analysis of syngeneic cell lines MCF10A, DCIS.com and MCF10CA and cross-referenced the targets using patient cohorts. By comparing gene expression between MCF10A and DCIS.com cell line, we identified ID2 as a regulator of DCIS initiation. ID2 promoted DCIS formation by enhancing cancer stemness of premalignant cells. On the other hand, we compared the DCIS.com and invasive breast cancer cell line, MCF10CA, and identified INHBA and GJB2 as novel regulators of aggressive phenotype. These 2 genes regulated migration, colonization and stemness of invasive cancer cells. Finally, we identified an ID2 inhibitor, natural compound Helichrysetin.
The brain is one of the major sites of metastasis in breast cancer and the pathological mechanism behind brain metastasis is poorly understood. We have found that the X-inactive specific transcript (XIST) was significantly down-regulated in brain metastases tissues and its expression levels had a significant inverse correlation with brain metastasis survival. XIST is encoded on the X chromosome and plays a critical role in X chromosome inactivation. Silencing XIST significantly promoted brain metastatic growth in xenograft model and XIST knockout in mice mammary gland accelerated primary tumor growth, as well as metastasis in the brain. Loss of XIST stimulated the epithelial-mesenchymal-transition and activated c-Met pathway and also augmented the secretion of exosomal microRNA-503, which triggered M1-M2 polarization of microglia. Furthermore, we identified fludarabine, purine analog antimetabolite, as a synthetic lethal drug for XIST-low breast tumor cells by sceening and found that fludarabine blocked brain metastasis in our animal model.Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment, and that the XIST-mediated pathway may serve as an effective target for the treatment of brain metastasis.
Notlar:
School code: 0248
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680902.1) | 680902-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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