The role of mammary epithelial cell (MEC) NF-kB in tumor progression in vivo is unknown, as murine NF-kB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-kB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-kB, the importance of MEC NF-kB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-kB (IkBaSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-kB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-kB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IkBaSR inhibited tumor stem cell pathways. IkBaSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-kB contributes to mammary tumorigenesis. As we show that NF-kB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-kB-dependent mammary tumorigenesis.

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The DNA damage response (DDR) activates downstream pathways including cell cycle checkpoints. The cyclin D1 gene is overexpressed or amplified in many human cancers and is required for gastrointestinal, breast, and skin tumors in murine models. A common polymorphism in the human cyclin D1 gene is alternatively spliced, resulting in cyclin D1a and D1b proteins that differ in their carboxyl terminus. Cyclin D1 overexpression enhances DNA damage-induced apoptosis. The role of cyclin D1 and the alternative splice form in regulating the DDR is not well understood. Herein cyclin D1a overexpression enhanced the DDR as characterized by induction of γH2AX phosphorylation, the assembly of DNA repair foci, specific recruitment of DNA repair factors to chromatin, and G 2 -M arrest. Cyclin D1 deletion in fibroblasts or small interfering RNA-mediated reduction of endogenous cyclin D1 in colon cancer cells reduced the 5-fluorouracil-mediated DDR. Mechanistic studies showed that cyclin D1a, like DNA repair factors, elicited the DDR when stably associated with chromatin. Cancer Res; 70(21); 8802-11. ©2010 AACR.

In this large data set, patients with 3 cm or more tumors showed a propensity for early recurrence, regardless of histology. Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease. There were no significant differences in morbidity or survival based on the surgical approach; however, local recurrence rates were highest for percutaneously ablated tumors.

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The Dachshund (dac) gene, initially cloned as a dominant inhibitor of the Drosophila hyperactive EGFR mutant ellipse, encodes a key component of the cell fate determination pathway involved in Drosophila eye development. Analysis of more than 2,200 breast cancer samples showed improved survival by some 40 months in patients whose tumors expressed DACH1. Herein, DACH1 and estrogen receptor-α (ERα) expressions were inversely correlated in human breast cancer. DACH1 bound and inhibited ERα function. Nuclear DACH1 expression inhibited estradiol (E2)-induced DNA synthesis and cellular proliferation. DACH1 bound ERα in immunoprecipitation-Western blotting, associated with ERα in chromatin immunoprecipitation, and inhibited ERα transcriptional activity, requiring a conserved DS domain. Proteomic analysis identified proline, glutamic acid, and leucine rich protein 1 (PELP1) as a DACH1-binding protein. The DACH1 COOH terminus was required for binding to PELP1. DACH1 inhibited induction of ERα signaling. E2 recruited ERα and disengaged corepressors from DACH1 at an endogenous ER response element, allowing PELP1 to serve as an ERα coactivator. DACH1 expression, which is lost in poor prognosis human breast cancer, functions as an endogenous inhibitor of ERα function.

AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

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