Both human and mouse cells express an alternatively spliced variant of BRCA1, BRCA1-⌬11, which lacks exon 11 in its entirety, including putative nuclear localization signals. Consistent with this, BRCA1-⌬11 has been reported to reside in the cytoplasm, a localization that would ostensibly preclude it from playing a role in the nuclear processes in which its full-length counterpart has been implicated. Nevertheless, the finding that murine embryos bearing homozygous deletions of exon 11 survive longer than embryos that are homozygous for Brca1 null alleles suggests that exon 11-deleted isoforms may perform at least some of the functions of Brca1. We have analyzed both the full-length and the exon 11-deleted isoforms of the murine Brca1 protein.Our results demonstrate that full-length murine Brca1 is identical to human BRCA1 with respect to its cell cycle regulation, DNA damage-induced phosphorylation, nuclear localization, and association with Rad51. Surprisingly, we show that endogenous Brca1-⌬11 localizes to discrete nuclear foci indistinguishable from those found in wild-type cells, despite the fact that Brca1-⌬11 lacks previously defined nuclear localization signals. However, we further show that DNA damage-induced phosphorylation of Brca1-⌬11 is significantly reduced compared to full-length Brca1, and that gamma irradiation-induced Rad51 focus formation is impaired in cells in which only Brca1-⌬11 is expressed. Our results suggest that the increased viability of embryos bearing homozygous deletions of exon 11 may be due to expression of Brca1-⌬11 and suggest an explanation for the genomic instability that accompanies the loss of full-length Brca1.Germ line mutations in BRCA1 predispose women to earlyonset breast and ovarian cancers (18,38). The BRCA1 gene is composed of 23 exons that encode a 1,863-amino-acid fulllength protein, over half of which is encoded by an unusually large exon, exon 11, which is 3.4 kb in length. In addition to the full-length BRCA1 protein, p220 BRCA1 , human cells contain alternatively spliced variants referred to as BRCA1-⌬11 (referred to here as p97 BRCA1 ) and BRCA1-⌬11b (referred to here as p110 BRCA1 ), which lack all and most of exon 11, respectively (54, 58). These isoforms arise from in-frame splicing events and retain the highly conserved amino-terminal RING finger and carboxyl-terminal BRCT domains found in fulllength BRCA1 but lack the nuclear localization signals previously identified in exon 11 (11,54,58). The abundant expression of p97 BRCA1 and p110 BRCA1 has been demonstrated in a variety of adult tissues, including the human mammary gland, in which transcripts encoding p110 BRCA1 are expressed at levels comparable to those encoding p220 BRCA1 (33,54,58). The observation that human BRCA1 is phosphorylated in response to UV light, ionizing radiation, and other agents that damage DNA, and the identification of BRCA1-interacting proteins such as RAD51 and RAD50-Mre11-p95 complexes that colocalize with BRCA1 following DNA damage have suggested a role for BRCA1 in DNA r...

Understanding the molecular pathways that contribute to the aggressive behavior of human cancers is a critical research priority. The SNF1/AMPK-related protein kinase Hunk is overexpressed in aggressive subsets of human breast, ovarian, and colon cancers. Analysis of Hunk -/-mice revealed that this kinase is required for metastasis of c-myc-induced mammary tumors but not c-myc-induced primary tumor formation. Similar to c-myc, amplification of the proto-oncogene HER2/neu occurs in 10%-30% of breast cancers and is associated with aggressive tumor behavior. By crossing Hunk -/-mice with transgenic mouse models for HER2/neu-induced mammary tumorigenesis, we report that Hunk is required for primary tumor formation induced by HER2/ neu. Knockdown and reconstitution experiments in mouse and human breast cancer cell lines demonstrated that Hunk is required for maintenance of the tumorigenic phenotype in HER2/neu-transformed cells. This requirement is kinase dependent and resulted from the ability of Hunk to suppress apoptosis in association with downregulation of the tumor suppressor p27 kip1 . Additionally, we find that Hunk is rapidly upregulated following HER2/neu activation in vivo and in vitro. These findings provide what we believe is the first evidence for a role for Hunk in primary tumorigenesis and cell survival and identify this kinase as an essential effector of the HER2/neu oncogenic pathway.

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.breast cancer ͉ knockout mice ͉ mouse models ͉ protein kinase

Gastrointestinal carcinoids are a biologically heterogeneous group of tumors, with variable clinical presentation and biologic behavior. Imaging can play an important role in multidisciplinary identification and management of this disease.