ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE

Abstract Ovarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy

Mitochondrial Control Region Alterations and Breast Cancer Risk: A Study in South Indian Population

<div><p>Background</p><p>Mitochondrial displacement loop (D-loop) is the hot spot for mitochondrial DNA (mtDNA) alterations which influence the generation of cellular reactive oxygen species (ROS). Association of D-loop alterations with breast cancer has been reported in few ethnic groups; however none of the reports were documented from Indian subcontinent.</p><p>Methodology</p><p>We screened the entire mitochondrial D-loop region (1124 bp) of breast cancer patients (n = 213) and controls (n = 207) of south Indian origin by PCR-sequencing analysis. Haplotype frequencies for significant loci, the standardized disequilibrium coefficient (D′) for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software.</p><p>Principal Findings</p><p>We identified 7 novel mutations and 170 reported polymorphisms in the D-loop region of patients and/or controls. Polymorphisms were predominantly located in hypervariable region I (60%) than in II (30%) of D-loop region. The frequencies of <i>310‘C’</i> insertion (<i>P</i> = 0.018), <i>T16189C</i> (<i>P</i> = 0.0019) variants and <i>310‘C’ins/16189C</i> (<i>P</i> = 0.00019) haplotype were significantly higher in cases than in controls. Furthermore, strong LD was observed between nucleotide position 310 and 16189 in controls (D′ = 0.49) as compared to patients (D′ = 0.14).</p><p>Conclusions</p><p>Mitochondrial D-loop alterations may constitute inherent risk factors for breast cancer development. The analysis of genetic alterations in the D-loop region might help to identify patients at high risk for bad progression, thereby helping to refine therapeutic decisions in breast cancer.</p></div

Novel mutations detected in mitochondrial D-loop region of breast cancer patients.

<p>rCRS: Revised Cambridge Reference Sequence.</p><p>IUPAC: International Union of Pure and Applied Chemistry.</p

Novel mutations observed in D-loop region of breast cancer patients:

<p>(A) 12 ‘C’ insertion; (B) A37G transition; (C) A238G transition; (D) C463T transition; (E) C566G transversion; (F) T16445C transition; (G) G16485A transition.</p

Graphical representation of minor allele frequencies of significant D-loop SNPs in breast cancer patients with different clinical parameters:

<p>(A) breast cancer stage; (B) menopausal status; (C) estrogen receptor status; (D) progesterone receptor status; (E) human epidermal growth factor receptor 2 status. Asterisk (*) indicates the significant difference (<i>P</i><0.05, as determined by the Student’s t-test) between patient groups with different clinical parameters. Percentage values were used for statistical analysis.</p

Linkage disequilibrium (LD) analysis of significant D-loop SNPs in cases and controls:

<p>Haploview plots are presented along the single nucleotide polymorphisms studied. The pair-wise linkage disequilibrium values (D′ = 0–100) of all significant SNPs are given in each diamond. A value of 100 represents maximum possible linkage disequilibrium.</p