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Miaw-Sheue Tsai

Publications and source records attributed to Miaw-Sheue Tsai.

4 recordsLinked to original sources
PubMed2026

Human MutLα activates methylpurine DNA glycosylase to induce alkylation damage cytotoxicity.

Alkylation chemotherapy is commonly used against tumors such as glioblastoma, yet resistance often develops through downregulation of mismatch repair (MMR). Previous work has established that loss of MMR prevents the excision of the thymine-containing strand across O 6meG-T mismatches, thereby avoiding the futile repair cycle that ultimately leads to cell death. Here, we provide an alternative explanation to this prevailing mechanism of chemoresistance by MMR loss. We found that the MMR protein MutLα physically and functionally interacts with the base excision repair (BER) enzyme methylpurine DNA glycosylase (MPG), which processes common alkylation adducts, such as 7meG and 3meA. Biochemical reconstitution demonstrates that MutLα activates MPG glycosylase activity by promoting MPG substrate binding, and enhancing MPG release from the abasic site product, thereby facilitating enzyme turnover. This glycosylase stimulation requires ATP hydrolysis as well as the MLH1-interacting region on MPG. Both MutLα or its ability to interact with MPG promote the generation of alkylation-induced abasic sites in cells, which contribute to the cytotoxicity of methyl methanesulfonate (MMS), an SN2 alkylating agent that does not produce O 6meG. Our results provide new insight into the mechanism of alkylation chemoresistance and uncover an unappreciated cross-talk between MMR and BER.

DNA repair↗
PubMed2003

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer.

The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorage-independent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.

Breast Neoplasms↗
PubMed2002

Cyr61 promotes breast tumorigenesis and cancer progression.

Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the 'normal' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that Cyr61 is sufficient to induce MCF-7 cells to grow in the absence of E2. Cyr61-transfected MCF-7 cells (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7 cells transfected with the vector DNA (MCF-7/V) remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ER alpha expression in MCF-7/Cyr61 cells is decreased although still functional. Moreover, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and antiestrogen-resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.

Adenocarcinoma↗
PubMed2002

Expression and regulation of Cyr61 in human breast cancer cell lines.

We have shown that Cyr61, an angiogenic regulator, is overexpressed in invasive and metastatic human breast cancer cells and tumor biopsies. We have further demonstrated that Cyr61 promotes acquisition of estrogen-independence and anti-estrogen resistance in vivo in breast cancer cells. Moreover, we have demonstrated that Cyr61 induces tumor formation and tumor vascularization in vivo, events mediated through the activation of the MAPK and the Akt signaling pathways. Here we investigate how Cyr61 expression is regulated in both estrogen receptor (ER)-positive and ER-negative breast cancer cells. We demonstrate that Cyr61 mRNA and protein expression is inducible by estrogen and anti-estrogens in ER-positive breast cancer cells. We show that a labile protein as well as a negative regulator might be involved in Cyr61 expression in estrogen-dependent breast cancer cells. Other important regulators of Cyr61 expression in breast cancer cells that we found are the phorbol ester TPA, vitamin D, and retinoic acid. TPA causes positive regulation of Cyr61 expression in ER-positive MCF-7 cells. Vitamin D induces a transient stimulatory effect on Cyr61 gene expression. Lastly, retinoic acid has a negative effect on Cyr61 expression and downregulates its expression in MCF-7 cells. Interestingly, most of these effects are not seen in aggressive breast cancer cells that do not express ER and express high levels of Cyr61, such as the MDA-MB-231 cells. Our results are in agreement with our knowledge that Cyr61 promotes tumor growth, and that tumor-promoting agents have a positive impact on cells that express low levels of Cyr61, such as the ER-positive breast cancer cells; however, these agents have no significant effect on cells that express high levels of Cyr61. Our findings suggest an association between increased Cyr61 expression and an aggressive phenotype of breast cancer cells.

Active Transport, Cell Nucleus↗