CHEK2 is a multiorgan cancer susceptibility gene

A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.     

MAT2A与NDRG2基因在结直肠癌中表达情况及临床意义的研究

目的研究MAT2A(甲硫氨酸腺苷转移酶2A)和NDRG2(N-Myc下游调节基因-2)基因在结直肠癌组织中的表达及两者的相关性,为结直肠癌的研究及治疗提供重要参考。方法选取68例术中切除结直肠癌组织及相应的癌旁组织标本,应用RT-PCR(逆转录-聚合酶链式反应)和Western blotting(蛋白质印迹法)检测结直肠癌中MAT2A和NDRG2表达水平。结果结直肠癌中MAT2A和NDRG2mRNA表达情况:MAT2A阳性表达率(66.2%,45/68)高于癌旁组织(7.4%,5/68);NDRG2阳性表达率(36.8%,25/68)低于癌旁组织(91.2%,62/68);两者的表达与患者年龄、性别、肿瘤生长位置等因素均无关,与癌肿临床分期、分化水平及淋巴结转移密切相关。癌肿组织中MAT2A蛋白表达量相较于癌旁组织明显增多(t=39.1152,P=0.0000),而癌肿组织中NDRG2蛋白表达量较癌旁组织明显降低(t=46.5103,P=0.0000);且在结直肠癌组织中两基因的表达可能有相关性(χ~2=7.41,P=0.009)。结论在结直肠癌组织中MAT2A表达增高,NDRG2表达下降,两者与肿瘤的发生发展具有一定相关性,推测可能与DNA甲基化异常有关,但具体机制仍待进一步研究。     

17β-Estradiol inhibits prostaglandin E2-induced COX-2 expressions and cell migration by suppressing Akt and ERK1/2 signaling pathways in human LoVo colon cancer cells

Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol treatment is sufficient to inhibit prostaglandin E2 (PGE2)-induced cellular motility in human colon cancer cells. Upregulation of cyclooxygenase-2 (COX-2) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. After administration of inhibitors including LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), or QNZ (NFκB inhibitor), we found that PGE2 treatment increases COX-2 via Akt and ERK1/2 pathways, thus promoting cellular motility in human LoVo cancer cells. We further observed that 17β-estradiol treatment inhibits PGE2-induced COX-2 expression and cellular motility via suppressing activation of Akt and ERK1/2 in human LoVo cancer cells. Collectively, these results suggest that 17β-estradiol treatment dramatically inhibits PGE2-induced progression of human LoVo colon cancer cells.     

Antiproliferative activity of 4-chloro-5,6-dihydro-2H-pyrans. Part 2: Enhancement of drug cytotoxicity

The Prins reaction was the basis to synthesize functionalized alkyl chlorodihydropyran derivatives. The inexpensive, stable, and environmentally friendly FeCl(3) promotes the cyclization. The method represents an efficient and regioselective manner to obtain in a single step chlorovinyl-TMS oxacycles. The in vitro antiproliferative activities of the compounds were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results show an enhancement in the cytotoxicity exhibited by the new analogs when compared to their parental compounds.     

Expression of cyclooxygenase-1 and 2 in naturally-occurring canine cancer

The purpose of this work was to determine cox-1 and cox-2 expression by immunohistochemistry in forms of naturally occurring canine cancer in order to identify animal systems for pre-clinical evaluation of cox inhibitors and cox-2 inhibitors in cancer. Canine lymphoma (LSA), prostatic carcinoma (PCA), osteosarcoma (OSA), oral melanoma (MEL), oral squamous cell carcinoma (SCC), oral fibrosarcoma (FSA), mammary carcinoma (MCA), and normal tissues were included. Cox-2 was expressed in epithelial tumors (17 of 26 SCC, 8 of 13 MCA, 5 of 9 PCA cases) and MEL (9 of 15 cases), but was generally absent in normal tissues. Cox-2 expression was minimal or absent in mesenchymal tumors and LSA. Cox-1 was expressed in normal epithelial tissues and in some osteoclast and osteoblast in bone, but was absent in normal lymph node. In conclusion, forms of canine cancer were identified for in vivo studies of the effects of cox inhibitors and selective cox-2 inhibitors on cancer.     

Protein kinase CK2 promotes cancer cell viability via up-regulation of cyclooxygenase-2 expression and enhanced prostaglandin E2 production

Augmented expression of protein kinase CK2 is associated with hyperproliferation and resistance to apoptosis in cancer cells. Effects of CK2 are at least partially linked to signaling via the Wnt/β-catenin pathway, which is dramatically enhanced in colon cancer. Cyclooxygenase-2 (COX-2), a Wnt/β-catenin target gene, has been associated with enhanced cancer progression and metastasis. However, the possibility that a connection may exist between CK2 and COX-2 has not been explored previously. Here we investigated changes in COX-2 expression and activity upon CK2 modulation and evaluated how these changes affected cell viability. COX-2 expression and cell viability decreased upon selective inhibition of COX-2 with SC-791 or CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), both in human colon (HT29-ATCC, HT29-US, DLD-1) and breast (ZR-75) cancer cells, as well as in human embryonic kidney (HEK-293T) cells. On the other hand, ectopic CK2α expression promoted up-regulation of COX-2 by activating the Wnt/β-catenin pathway in HEK-293T cells. Noteworthy, over-expression of either CK2α, β-catenin or COX-2, as well as supplementation of the medium with prostaglandin E2 (PGE2), all were individually sufficient to overcome limitations in cell viability triggered by CK2 inhibition either upon addition of DMAT or over-expression of a dominant negative CK2α variant. Altogether, these findings provide new insight to the role of CK2 in cancer by up-regulating COX-2 expression and thereby PGE2 production.     

Cyclooxygenase-2 in cancer: A review

Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κβ are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radio- and chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.     

IARS2在胃癌预后中的临床应用

为检测IARS2和MYO5B在胃癌组织中的表达并探讨IARS2表达与胃癌患者临床病理特征及预后的关系,本研究使用荧光定量PCR (quantitative polymerase chain reaction, qRT-PCR)及Western blotting检测30例胃癌组织和癌旁组织中IARS2和MYO5B的表达,使用线性回归分析两者m RNA表达相关性。使用免疫组化方法检测86对胃癌组织及癌旁组织中IARS2蛋白的表达情况,根据免疫组化IARS2表达情况将胃癌患者分为IARS2阳性组和阴性组,比较两组患者临床病理特征及预后情况。结果发现,较之癌旁组织,IASR2在胃癌组织中显著高表达(p<0.05),而MYO5B在胃癌组织中显著低表达(p<0.05),且两者表达负相关(r=0.5768, p=0.0008)。免疫组化显示IASR2阳性细胞在胃癌组织中的阳性率为70.9%。IASR2高表达提示更高的胃癌淋巴结转移(p=0.041)和TNM分期(p=0.004)及更低的患者术后5年总生存率(p=0.000 6)。研究提示IARS2在胃癌组织中高表达,可作为评估胃癌预后的标志物。     

Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer

Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK), including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR) and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC) patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2), a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.     

MMP-2和TIMP-2基因启动子区多态性与卵巢上皮性癌关系的研究

为探讨MMP-2和TIMP-2基因启动子区单核苷酸多态性(SNPs)与卵巢上皮性癌发病风险的关系, 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测了246例卵巢上皮性癌患者和324例对照妇女的MMP-2 C-1306T、C-735T和TIMP-2 G-418C 3个SNPs的基因型。结果显示, MMP-2 C-1306T SNP的等位基因及基因型频率分布在卵巢癌与对照组间无显著差异(P=0.55和P=0.42); 但卵巢癌组MMP-2 C-735T SNP的C等位基因和C/C基因型频率(80.7%和66.7%)明显高于对照组(75.5%和55.9%), 与T/T+C/T基因型比较, 携带C/C基因型可以显著增加卵巢癌的发病风险(OR=1.58, 95% CI=1.12~2.23), 进一步分层分析显示, C/C基因型主要与宫内膜样癌和年龄≥50岁妇女的发病风险显著相关, OR值分别为1.69(95%CI=1.03~2.79)和1.71(95% CI=1.14~2.57); 对MMP-2 C-1306T、C-735T 2个SNPs的单体型分析显示, 4种单体型频率(T_-1306-T_-735、T_-1306-C_-735、C_-1306-T_-735和C_-1306-C_-735)在两组间分布无显著差异(P=0.24); 虽然TIMP-2 G-418C SNP的等位基因及基因型频率在卵巢癌组与对照组间分布无显著性差异(P=0.33和P=0.47), 但以病理类型分层分析显示, 携带TIMP-2 G-418G/G基因型有增加宫内膜样癌发病风险的趋势(OR=1.62, 95%CI=0.94~2.78)。以上结果提示, MMP-2基因启动子区C-735T SNP的C/C基因型可能是卵巢上皮性癌发病的潜在危险因素, 而C-1306T SNP可能与卵巢上皮性癌的发病风险无关; TIMP-2 G-418C SNP可能与不同病理类型的卵巢上皮性癌发病风险有关。     

BRCA2 mutations and triple-negative breast cancer

Recently, BRCA1 germline mutations were found in a high proportion (14-34%) of patients with triple-negative breast cancer (TNBC). BRCA2 was either not analyzed or showed much lower mutation frequencies. Therefore, we screened a group of TNBC patients (n = 30) of white European descent for mutations in BRCA2 as well as in BRCA1. Cases were unselected for age of disease-onset (median age at breast cancer diagnosis was 58 years, ranging from 37 to 74 years), family history of cancer and BRCA1 and BRCA2 mutation status. Half of the patients (15/30) showed a family history of breast and/or ovarian cancer. A high frequency of deleterious germline mutations was observed in BRCA2 (5/30; 16.7%), and only one case showed a BRCA1 mutation (3.3%). Although the study group was small, these results point to BRCA2 mutations being important in TNBC.     

Lung tumor-associated osteoblast-derived bone morphogenetic protein-2 increased epithelial-to-mesenchymal transition of cancer by Runx2/Snail signaling pathway

Bone is a frequent target of lung cancer metastasis and is associated with significant morbidity and a dismal prognosis. Interaction between cancer cells and the bone microenvironment causes a vicious cycle of tumor progression and bone destruction. This study analyzed the soluble factors secreted by lung tumor-associated osteoblast (TAOB), which are responsible for increasing cancer progression. The addition of bone morphogenetic protein-2 (BMP-2), present in large amounts in TAOB conditioned medium (TAOB-CM) and lung cancer patient sera, mimicked the inductive effect of TAOB-CM on lung cancer migration, invasion, and epithelial-to-mesenchymal transition. In contrast, inhibition of BMP by noggin decreases the inductive properties of TAOB-CM and lung cancer patient sera on cancer progression. Induction of lung cancer migration by BMP-2 is associated with increased ERK and p38 activation and the up-regulation of Runx2 and Snail. Blocking ERK and p38 by a specific inhibitor significantly decreases cancer cell migration by inhibiting Runx2 up-regulation and subsequently attenuating the expression of Snail. Enhancement of Runx2 facilitates Rux2 to recruit p300, which in turn enhances histone acetylation, increases Snail expression, and decreases E-cadherin. Furthermore, inhibiting Runx2 by siRNA also suppresses BMP-2-induced Snail up-regulation and cell migration. Our findings provide novel evidence that inhibition of BMP-2 or BMP-2-mediated MAPK/Runx2/Snail signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.     

Synthesis and antiproliferative activity of (2R,3R)-disubstituted tetrahydropyrans. Part 2: Effect of side chain homologation

In this study, we synthesized a series of enantiomerically pure (2R,3R)- and (2R,3S)-disubstituted tetrahydropyrans bearing a CH2O spacer group on the side chain at position 2 of the heterocyclic ring. The in vitro antiproliferative activities of the compounds were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results point out the relevance for antiproliferative activity of the distance between the heterocycle and the unsaturated group.     

Antiproliferative activity of 2-alkyl-4-halopiperidines and 2-alkyl-4-halo-1,2,5,6-tetrahydropyridines in solid tumor cell lines

A series of trans-2-alkyl-4-halopiperidines and 2-alkyl-4-halo-1,2,5,6-tetrahydropyridines were prepared by means of an iron(III) catalyzed process. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). The results on the biological activity revealed that, in general, the 2-alkyl-4-halo-1,2,5,6-tetrahydropyridine analogs are more potent than the trans-2-alkyl-4-halopiperidine derivatives. A remarkable selectivity of the aza compound 5f for the resistant cell line WiDr was observed. Cell cycle studies revealed a G(2)/M phase arrest for 5f.     

HPC2 variants and screen-detected prostate cancer

Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.     

Expressions of ER,PR, HER-2, COX-2, and VEGF in Primary and Relapsed/Metastatic Breast Cancers

In the present study, we evaluated expressions of estrogen receptor (ER), progestin receptor (PR), human epidermal growth factor receptor-2 (HER-2), cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF) in primary and relapsed/metastatic breast cancers to elucidate the clinical significance of these markers. The markers were evaluated by immunohistochemistry in specimens of 50 patients with primary or metastatic breast cancer. Positive rates of ER were significantly (p = 0.002) higher in primary versus relapsed/metastatic breast cancer (70 vs. 38 %, respectively). The VEGF positive expression rates were also significantly higher in primary versus metastatic cancer (82 vs. 38 %, respectively; p < 0.001). By contrast, positive rates of HER-2 and COX-2 were not significantly different between different types of cancer. COX-2 correlated with HER-2 expression in both primary and relapsed/metastatic focuses of breast cancer. COX-2 also correlated with VEGF expression in primary breast cancer. Expressions of ER, PR, HER2, and COX-2 did not correlate between primary and relapsed/metastatic breast cancers, indicating that the treatment decision should be made according to the status of these markers in relapsed/metastatic focuses. The total change rates of ER, PR, HER-2, COX-2, and VEGF were 26, 18, 10, 30, and 58 %, respectively. In conclusion, HER-2 and COX-2, along with VEGF, appear to play a role in the development and progression of breast cancer. In addition, all of the studied markers may serve as indicators of prognosis.     

ErbB2 down-regulates microRNA-205 in breast cancer

Gene amplification and protein overexpression of erbB2 (Her2/neu) has been observed in approximately 20–30% of breast cancers. ErbB2-positive breast cancer is tend to be more aggressive than other types of breast cancer and therefore further investigation on the signaling pathways of erbB2 is needed for the therapeutic target for breast cancer treatment. Here we report that microRNA-205 (miR-205), a molecule also reported to be associated with breast cancer, is negatively regulated by erbB2 overexpression. Breast epithelial cells exogenously overexpressed with erbB2 decreased the expression of miR-205, whereas increased the expression of cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6). The decreased expression of miR-205 slightly increased by the transfection of erbB2 siRNA into the erbB2-overexpressing breast cancer epithelial cells. Overexpression of erbB2 enabled breast epithelial cells to grow anchorage-independently in soft agar, and the transfection of the precursor of miR-205 into the cells leaded to the decrease in the ability to grow in soft agar. These results suggest that down-regulation of miR-205 in erbB2-overexpressing breast epithelial cells is essential for erbB2-induced tumorigenesis, and miR-205 may have the potential to be a novel important alternative therapeutic target for erbB2-positive breast cancer.     

TIE2-high cervical cancer cells promote tumor angiogenesis by upregulating TIE2 and VEGFR2 in endothelial cells

Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2), the receptor for angiopoietins, has been found highly expressed in cervical cancer and associated with poor prognosis. However, the potential role of tumoral TIE2 in cervical cancer angiogenesis and the underlying mechanisms remain unexplored. Here, based on multicolor immunofluorescence of 64 cervical cancer tissues, we found that TIE2 level in cervical cancer cells was positively related to shorter survival and higher microvessel density in tumor. In vitro and in vivo experiments verified that TIE2-high cervical cancer cells could promote tumor angiogenesis. TIE2-high tumor cells induced an amplified expression of TIE2 and vascular endothelial growth factor receptor 2(VEGFR2) in HUVECs to promote angiogenesis via TIE2 -AKT/MAPK signals, which could be reversed or partially reversed by TIE2, AKT or MAPK inhibitors and activated by angiopoietin-1 and angiopoietin-2. In conclusion, TIE2-high cervical cancer cells promote tumor angiogenesis by upregulating TIE2 and VEGFR2 in endothelial cells via TIE2-AKT/MAPK axis inside tumor cells.     

MicroRNA-101 inhibits angiogenesis via COX-2 in endometrial carcinoma

Abnormal angiogenesis is critically involved in tumor progression and metastasis including endometrial cancer and is regulated by microRNAs such as microRNA-101 (miR-101). We hypothesize that miR-101 expression is disrupted in endometrial cancer and modulation of miR-101 levels is sufficient to regulate tumor growth through angiogenesis. We examined the expression levels of miR-101 and factors involved in angiogenesis in the patients with endometrial cancer. We also overexpressed or inhibited miR-101 in RL-95-2 cells and examined their effects on cell toxicity and tumor growth. Finally, we determined if miR-101 regulated tumorigenesis through cyclooxygenase-2 (COX-2). We found that miR-101 levels were significantly reduced. Factors involved in angiogenesis included vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and aromatase (P450arom), which were increased in endometrial carcinoma. Modulation of miR-101 level was sufficient to affect tumor growth. Finally, we found that the effects of miR-101 inhibition on tumor growth were suppressed by COX-2 inhibition. Our results suggest that modulating miR-101 and COX-2 levels or their activity may be a potential therapeutic strategy for endometrial cancer.     

Murine Double Minute 2 Gene (MDM2) rs937283A/G variant significantly increases the susceptibility to breast cancer in Saudi Women

Breast cancer is predominant causes of mortality in women worldwide. Genetic polymorphisms have a significant role in breast cancer aetiology. TP53 and its inhibitor the murine double minute 2 (MDM2) genes encode proteins that have crucial functions in the DNA damage response. The allelic variations within these genes could influence the susceptibility to breast cancer. MDM2 promotor polymorphism rs937283A/G has a role in susceptibility to cancer and modifies the promoter activity. In the present case-control study, the association of MDM2 rs937283A/G polymorphism and breast cancer susceptibility in Saudi women with samples of 137 breast cancer patients, and 98 healthy controls were explored. MDM2 gene polymorphism rs937283A/G was genotyped by polymerase chain reaction restriction fragment length polymorphism and confirmed by sequencing. The results revealed that rs937283A/G variant is significantly increases the risk of breast cancer in Saudi women (p-value = 0.0078). Moreover, rs937283A/G polymorphism was associated with high risk of breast cancer in estrogen positive breast cancer patients (p-value = 0.0088), progesterone positive breast cancer patients (p-value = 0.0043), human epidermal growth factor receptor 2 negative breast cancer patients (p-value = 0.0026), and triple negative breast cancer patients where (p-value = 0.0003). Positive association between increased breast cancer risk and rs937283 variant in premenopausal Saudi women, below 50 years of age, was demonstrated (p-value = 0.0023). Collectively, MDM2 rs937283A/G polymorphism could act as a possible biomarker for breast cancer susceptibility in Saudi women.