Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse

Abstract

Annexin 7 (ANX7) acts as a tumor suppressor gene in prostate cancer, where loss of heterozygosity and reduction of ANX7 protein expression is associated with aggressive metastatic tumors. To investigate the mechanism by which this gene controls tumor development, we have developed an Anx7(؉͞؊) knockout mouse. As hypothesized, the Anx7(؉͞؊) mouse has a cancer-prone phenotype. The emerging tumors express low levels of Anx7 protein. Nonetheless, the wild-type Anx7 allele is detectable in laser-capture microdissection-derived tumor tissue cells. Genome array analysis of hepatocellular carcinoma tissue indicates that the Anx7(؉͞؊) genotype is accompanied by profound reductions of expression of several other tumor suppressor genes, DNA repair genes, and apoptosis-related genes. In situ analysis by tissue imprinting from chromosomes in the primary tumor and spectral karyotyping analysis of derived cell lines identify chromosomal instability and clonal chromosomal aberrations. Furthermore, whereas 23% of the mutant mice develop spontaneous neoplasms, all mice exhibit growth anomalies, including gender-specific gigantism and organomegaly. We conclude that haploinsufficiency of Anx7 expression appears to drive disease progression to cancer because of genomic instability through a discrete signaling pathway involving other tumor suppressor genes, DNA-repair genes, and apoptosis-related genes.hepatocellular carcinoma ͉ lymphosarcoma of the thymus ͉ SKY analysis ͉ cDNA microarray A nnexin 7 (ANX7) is a newly described tumor suppressor gene (TSG) for prostate cancer in men, featuring loss of heterozygosity and reduced ANX7 § protein expression in a large fraction of archived metastatic tumors (1). ANX7 maps to chromosome 10q21, where unknown TSGs had been postulated but not yet identified (2-4). In a previous work, we established an Anx7(ϩ͞Ϫ) knockout mouse, in which Ca 2ϩ -dependent endocrine secretory defects were identified (5). We also noted substantial reductions of Anx7 expression in the pancreas, heart, and other tissues. The nullizygous Anx7(Ϫ͞Ϫ) knockout could not be studied. The embryo failed to develop beyond embryonic day 10 in utero. However, as the Anx7(ϩ͞Ϫ) colony aged, we began to observe an increasing frequency of disparate tumors (6). The mechanism of tumorigenesis in humans and mice often differ (7). Therefore, given the apparent TSG-like ANX7 parallel between tumors in mice and humans, we felt compelled to investigate the mechanisms of tumor transformation in the Anx7(ϩ͞Ϫ) mouse model.Mechanistically, we reasoned that we might be able to distinguish between a Knudson two-hit model, as might be considered possible based on the human prostate tumor data, and a haploinsufficiency model, based on low Anx7 protein levels in otherwise normal knockout-mouse tissues. We find that the data clearly support a haploinsufficiency model for tumor development in the knockout mouse. In addition, the tumors demonstrate an increased level of genetic instability, based on spectral karyotyping (SKY) analysis of primary tumors...

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

“…This prompts us to speculate that a compromised NHERF signaling may promote breast cancer initiation and progression by a haploinsufficiency mechanism (Kucherlapati et al, 2002;Magee et al, 2003;Srivastava et al, 2003;Staff et al, 2003). This may also in part explain the relatively low rate of NHERF biallelic inactivation.…”

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

“…Consistent with a presumably restored PTEN function by WT-ANXA7 in our study, ANXA7 deficiency in Anxa7(1/2) murine model resulted in PTEN inhibition. 1 Remarkably, the binding partner of ANXA7, galectin-3, was recently identified as a novel PTEN regulator. 47 These data suggested that WT-ANXA7 could intervene with the p53/PTEN control over RB-mediated cell survival, thereby opposing pathologic AR signaling in prostate cancer cells.…”

“…For instance, deficiency of RB1 reduces cell size, whereas PTEN increases cell size. [14][15][16] Growth anomalies in cancer-prone Anxa7(1/2) mice included organomegaly and betacell hypertrophy, 1,17 suggesting that ANXA7 can also be involved in cell size regulation.…”

“…In addition to Ca 21 -activated GTPase activity as well as involvement in membrane fusion and exocytosis, ANXA7 demonstrated tumor suppressor function in murine model 1 and in human prostate and breast cancers. 2,3 Our large-scale study on ANXA7 protein expression in different cancers 4 identified a drastic ANXA7 loss in the hormone-refractory prostate cancers as well as an abundant ANXA7 presence in the adrenal gland, a major source of sex hormone precursors.…”

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

“…Human ANXA7 has shown a tumor suppressor role in multiple studies that involved prostate cancer (Srivastava et al, 2003(Srivastava et al, , 2007Torosyan et al, 2009). In addition, Anxa7( ± ) mice have a cancer-prone phenotype, leading to a spectrum of tumors including prostate cancer (Srivastava et al, 2003).…”