SummaryMany solid cancers have an expanded CD44+/hi/CD24−/low cancer stem cell (CSC) population, which are relatively chemoresistant and drive recurrence and metastasis. Achieving a more durable response requires the development of therapies that specifically target CSCs. Recent evidence indicated that inhibiting the SUMO pathway repressed tumor growth and invasiveness, although the mechanism has yet to be clarified. Here, we demonstrate that inhibition of the SUMO pathway repressed MMP14 and CD44 with a concomitant reduction in cell invasiveness and functional loss of CSCs in basal breast cancer. Similar effects were demonstrated with a panel of E1 and E3 SUMO inhibitors. Identical results were obtained in a colorectal cancer cell line and primary colon cancer cells. In both breast and colon cancer, SUMO-unconjugated TFAP2A mediated the effects of SUMO inhibition. These data support the development of SUMO inhibitors as an approach to specifically target the CSC population in breast and colorectal cancer.
CT and SRS are complementary in making the diagnosis of SBNET, with CT giving more precise anatomical detail, while SRS helps to confirm that lesions are NETs and is useful for identifying occult extrahepatic sites of metastatic disease. However, 10-15 % of SBNETs were not identified by either test preoperatively, and therefore surgical exploration still plays an important role in making the diagnosis in these patients.
Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers and ChIP-seq confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, p < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, p < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated though the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.
Background Meckel’s diverticulum is a common anomaly of the GI tract, which occasionally gives rise to cancer. The most frequent tumor affecting these diverticula are neuroendocrine tumors (NETs), and whether these should be treated in similar fashion as small bowel NETs or appendiceal NETs is unclear. Methods A retrospective chart review was conducted at a single academic medical center between 1998–2012. Demographic, radiologic, biochemical, and clinicopathologic data were collected, as well as status at last follow-up. Results Seven patients were identified with NETs involving Meckel’s diverticula, including one with limited information other than the management of her late metastases. Of the 6 other patients, all had involvement of regional nodes, including 3 patients with tumors <2 cm in size, and 4 had liver metastases at presentation. Conclusions NETs in Meckel’s diverticula are rare tumors, but when they develop, are often associated with nodal metastases and liver metastases, even when the tumors are small. Therefore, the optimal management of these NETs is small bowel resection with regional lymphadenectomy, and debulking of liver metastases where feasible.
Background Management of Graves disease includes antithyroid drugs, 131I therapy, or thyroidectomy. Our aim was to review our institutional experience with definitive treatments for Graves disease. Methods This was a retrospective review of patients undergoing 131I therapy (n = 295) or thyroidectomy (n = 103) for Graves disease (2003–2015). Demographic, clinical, pathology, and outcome data were collected from institutional databases. Results 131I therapy patients were older (39.1 years vs 33.4 years, P = .001). There was no difference in the presence of ophthalmopathy between groups. A larger proportion of children received thyroidectomy than 131I therapy (17.1% vs 9.2%, P = .026). The success rate of the first 131I therapy dose was 81.4%. Overall success rate, including additional doses, was 90.1%. Rapid turnover of iodine correlated with 131I therapy failure (58.3% rapid turnover failure vs 14.9% non–rapid turnover failure, P < .05). All surgical patients underwent total or near-total thyroidectomy. 131I therapy complications included worsening thyrotoxicosis (1%) and deteriorating orbitopathy (0.7%). Operative complications were higher than 131I therapy complications (P < .05) but were transient. There was no worsening orbitopathy or recurrent Graves disease among surgical patients. Conclusion A higher proportion of pediatric Graves disease patients underwent thyroidectomy than 131I therapy. Rapid turnover suggested more effective initial management with operation than 131I therapy. Although transient operative complications were high, 131I therapy complications included worsening of Graves orbitopathy among those with pre-existing orbitopathy.
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