IGF-1 and BRCA1 signalling pathways in familial cancer

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: .
The Lancet Oncology (Impact Factor: 24.73). 12/2012; 13(12):E537-44. DOI: 10.1016/S1470-2045(12)70362-5
Source: PubMed

ABSTRACT The insulin-like growth factor (IGF) system has a direct effect on cellular proliferation and survival, and interacts with genetic and environmental factors implicated in causing cancer. Experimental, clinical, and epidemiological evidence show that the IGF signalling pathways are important mediators in the biochemical and molecular chain of events that lead from a phenotypically normal cell to one harbouring neoplastic traits. BRCA1 and BRCA2 have an important role in the development of hereditary and sporadic breast and ovarian cancer. Recent evidence suggests that risk of cancer conferred by BRCA mutations can be modified by genetic and environmental factors, including ambient concentrations of IGF-1 and polymorphisms in IGF system components. This Review addresses interactions between the IGF and BRCA1 signalling pathways, and emphasises the convergence of IGF-1-mediated cell survival, proliferative pathways, and BRCA1-mediated tumour protective pathways. Understanding the complex interactions between these signalling pathways might improve our understanding of basic molecular oncology processes and help to identify new molecular targets, predictive biomarkers, and approaches for optimising cancer therapies.


Available from: Haim Werner, May 30, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among various auto/paracrine growth-regulating signaling pathways an important role belongs to that of insulin-like growth factors (IGFs) and insulin. IGF-signaling system is actively involved in the regulation of both normal ovarian function and ovarian tumor growth. On the one hand, all members of this system are expressed in malignant ovarian epithelial cells, and the prognostic significance of this expression has been revealed for some of them in ovarian cancer patients in several studies. On the other hand, circulating IGFs/IGFBPs levels have not been undoubtedly associated with ovarian cancer risk or disease progression, but some of them can be regarded as supplementary serological ovarian cancer markers. An important route to the clinical application of IGF-signaling system studies in ovarian cancer is the growing possibility of using specific molecular targeted agents to suppress its growth-stimulating and other activities. However, the introduction of such agents to practical oncology has met serious problems, with the main difficulties resulting from the absence of reliable predictive molecular markers and metabolic side effects due to the tight connection between IGF-signaling and insulin-regulated processes. The prognostic and diagnostic values of various IGF system components and the current state of corresponding molecular targeted therapies development for ovarian cancer are reviewed.
    05/2015; DOI:10.1515/dmdi-2014-0037
  • [Show abstract] [Hide abstract]
    ABSTRACT: Both hereditary factors (e.g., BRCA1) and nicotinamide adenine dinucleotide (NAD)-dependent metabolic pathways are implicated in the initiation and progression of ovarian cancer. However, whether crosstalk exists between BRCA1 and NAD metabolism remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation and promoter methylation) were accompanied by elevated levels of NAD; (ii) the knockdown or overexpression of BRCA1 was an effective way to induce an increase or decrease of nicotinamide phosphoribosyltransferase (Nampt)-related NAD synthesis, respectively; and (iii) BRCA1 expression patterns were inversely correlated with NAD levels in human ovarian cancer specimens. In addition, it is worth noting that: (i) NAD incubation induced increased levels of BRCA1 in a concentration-dependent manner; (ii) Nampt knockdown-mediated reduction in NAD levels was effective at inhibiting BRCA1 expression; and (iii) the overexpression of Nampt led to higher NAD levels and a subsequent increase in BRCA1 levels in primary ovarian cancer cells and A2780, HO-8910 and ES2 ovarian cancer cell lines. These results highlight a novel link between BRCA1 and NAD. Our findings imply that genetic (e.g., BRCA1 inactivation) and NAD-dependent metabolic pathways are jointly involved in the malignant progression of ovarian cancer.
    Cell cycle (Georgetown, Tex.) 08/2014; 13(16):2564-2571. DOI:10.4161/15384101.2015.942208 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Age and physiological status, like menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently implanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53 null mammary tissue fragments and monitored for 1 year. Tumors arose sooner from adult hosts (AH) compared to juvenile hosts (JH). However, compared to AH tumors, JH tumors grew several times faster, were more perfused, exhibited a 2-fold higher mitotic index and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were ER positive (80% JH vs 70% AH) but JH tumors were significantly more ER immunoreactive (p=0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across data sets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.
    Cancer Research 10/2014; 74(23). DOI:10.1158/0008-5472.CAN-14-1440 · 9.28 Impact Factor