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View the Table of Contents for the March 15 issue of Cancer Research
Page 2089
Cancer development involves a succession of genetic mutations and chromosome rearrangements. Interaction between BRCA2 and the RAD51 homologous recombination (HR) protein suggests a link between HR defects and cancer progression. By investigating mice and cell lines deficient for the HR gene Rad51d, Smiraldo et al. report that RAD51D is essential for maintaining chromosome stability. Mitotic chromosome analysis revealed a significant increase in structural chromosome aberrations and, consistent with the role of RAD51D in HR repair, mutant cells were hypersensitive to DNA damaging agents. These findings suggest potential mechanisms for episodic chromosome instability during carcinogenesis.
Page 2139
BRCA1 product plays a role in the multi step X chromosome inactivation (XCI) process, supporting XIST mRNA localization on the inactive X. To clarify the XCI pattern and defects in breast cancer, Sirchia et al. investigated, by a combined genetic and epigenetic approach, a panel of BRCA1wt and BRCA1-/- breast cancer cell lines and non-cultured primary tumors. The authors found that in spite of the presence of two or more X chromosomes, none of them was functionally inactivated, irrespective of BRCA1 status and XIST expression. This finding has implications on the occurrence of different mechanisms mediating breast tumorigenesis through X-linked genes overexpression.
Page 2277
Hypoxia Inducible Factors (HIFs) are essential transcriptional regulators critical for adaptation to hypoxic stress in rapidly growing tissues such as tumors. HIF activity is regulated by the related HIF-1a and HIF-2a subunits, which are frequently overexpressed in cancer cells. To dissect the relative tumor-promoting functions of HIF-1a and HIF-2a, Covello et al. replaced HIF-1a expression with HIF-2a by creating a novel “knock-in” allele (KI) in murine embryonic stem cells. Compared to controls, subcutaneous teratomas derived from KI embryonic stem cells were larger and more proliferative, had increased microvessel density, and exhibited increased expression of VEGF and TGF-a. These and other data indicate that HIF-2a promotes tumor growth more effectively than HIF-1a, apparently through altered expression of specific HIF target genes.
Page 2287
Androgen receptor (AR) is the key player for the initiation of prostate cancer and relapse transition after hormone therapy. To search new effective agents targeting down-regulation of AR, Cha et al., found a natural compound, emodin, that inhibits AR transcriptional activity by preventing its nuclear translocation and induces AR degradation through proteasome-mediated pathway. Emodin-mediated down-regulation of AR results in inhibiting prostate cancer cell proliferation in vitro and inhibiting tumor growth, and prolonging survival of transgenic mice in vivo. Emodin may have the potential as a novel anti-AR therapeutic and preventive agent for prostate cancer.
Page 2412
The role played by the activating V599EB-Raf mutation in melanoma tumorigenesis is currently unknown. To identify its functional significance, Sharma et al. used a combination of siRNA-mediated knockdown and pharmacological inhibition of V599EB-Raf in developing and pre-existing tumors. Targeting prior to tumor formation reduced the growth potential of melanoma cells inhibiting tumor development. In contrast, inhibition in pre-existing tumors reduced cell proliferation and prevented further vascular development, mediated through decreased VEGF secretion. Thus, these studies identify the mechanistic underpinnings by which mutant V599EB-Raf promotes melanoma development. Furthermore, they demonstrate the therapeutic potential of targeting this protein to inhibit melanoma tumor growth.