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• W2967362008 abstract "Author(s): Shah, Manav | Abstract: The malignant aspect of tumorigenesis in breast cancer is initiated when human mammary epithelial cells (HMEC) first immortalize (gain the ability to proliferate indefinitely) and subsequently undergo oncogenic activation. Our laboratory has developed a two-step HMEC immortalization process that we believe accurately models early breast cancer progression. Normal finite pre-stasis HMEC must overcome two distinct senescence barriers to achieve full immortality: stasis (stress-associated senescence) and replicative senescence, respectively. HMEC bypass stasis, and become post-stasis, when errors in the retinoblastoma pathway are present. Replicative senescence, a product of continuously shortening telomeres producing telomere dysfunction, is overcome by the reactivation of telomerase. Our lab has called HMEC that acquire the error allowing telomerase expression conditionally immortal (CI); CI cells may still have low telomerase expression. Full immortality is achieved when sufficient telomerase expression exists to maintain short stable telomeres following a process we have called conversion. The transcriptional coactivator YAP, upregulated in several human cancers, is closely correlated with a variety of oncogenic effects including proliferation and induction of cancer stem cell (CSC) properties. Our preliminary data have shown that YAP-transduced post-stasis HMEC expressed properties of CI cells. Growth curves indicated that some cell lines achieved full immortality; however, these cells had acquired an additional error – amplified expression of c-Myc, an oncogene known to induce telomerase in post-stasis or CI cells. The absence of uniform immortalization in the YAP-transduced cells suggests that YAP causes post-stasis HMEC to become conditionally immortal. This is further supported given that YAP-transduced post-stasis HMEC have decreased levels of the lncRNA MORT and rapidly go through conversion when p53 function is abrogated, well-documented attributes of CI HMEC. Previous studies have also reported that YAP controls the differentiation of breast progenitor cells; as a result, it is likely that YAP plays a role in inducing CSC phenotypes. In this study, we attempt to gain a greater understanding of YAP’s role in HMEC immortalization and induction of CSC properties in early breast cancer progression. We measured gene expression levels and attempted to identify proteins indicative of a CSC phenotype in YAP-transduced post-stasis HMEC. Our initial results did not reveal an association between YAP and HMEC conditional immortality or induction of CSC attributes in the cultures examined. However, using a YAP construct that promotes nuclear localization (where YAP is most active) has led to a potentially promising YAP-derived cell line that we presume to be immortal. We go on to demonstrate that YAP may be acting via non-transcriptional oncogenic roles in our HMEC specimens. Thus, we recommend future studies into YAP and the HMEC immortalization process given that they are promising targets for breast cancer prevention therapies." @default.
• W2967362008 created "2019-08-22" @default.
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• W2967362008 date "2019-08-07" @default.
• W2967362008 modified "2023-09-27" @default.
• W2967362008 title "Investigating YAP’s role in Human Mammary Epithelial Cell (HMEC) Immortalization and Cancer Stem Cell (CSC) Phenotype Acquisition during Early Breast Cancer Progression" @default.
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