Breast cancer susceptibility genes in estrogen metabolizing pathway in a southern Indian population

Ali

et al. 2019

IJMS

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages. of sulfonate (SO 3 − ) group enhances the substrate hydrophilic potentiality or polarity and generates less toxic metabolites, and finally facilitates them for excretion [5,11]. In some cases, sulfonation of exogenous compounds turns them into active mutagens and carcinogens [12][13][14], although it sometimes acts as a chemical defense mechanism against xenobiotics [15].Recently, mutation at 213 positions of SULT1A1 exon 7 (rs9282861) [16,17] was reported by multiple studies to be involved in breast cancer progression [18], especially among the postmenopausal Asian women [19,20]. A meta-analysis showed that polymorphic rs9282861 has a significant association with bladder cancer [21], while a small scale case-control study found a significant association with the prevalence of intestinal cancer [22]. The significant association was also found for developing head and neck cancer [23], lung cancer [11,17,24], and also accountable for acute leukemia in infants and acute myeloid leukemia [25]. Patients having rs9282861 mutation, which caused the change of an amino acid from arginine to histidine at the 213th position (R213H), may have a higher susceptibility for developing esophageal cancer, due to the lower enzymatic activity and thermal stability that affect the procarcinogens metabolisms [4,8,26,27], including various steroid hormones, neurotransmitters, and non-opiateanalgesics [28,29]. Furthermore, the substitution occurred with amino acid having the same side chain polarity, although the mutation was reported to reduce the binding affinity of various substrates, as well as their pharmacokinetic properties [2...

mentioning

confidence: 99%

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confidence: 99%

Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding

Ali

et al. 2019

IJMS

“…Genetic variations (singlenucleotide polymorphisms) in the CYPP450 genes can modulate metabolic activities during the transformation of substances. This may either increase or reduce exposure to estrogenic metabolites [10,11]. Allele distribution in CYP450 genes differs between populations, and these genes are of clinical importance as they can be studied to understand disease development and progression [12].…”

Section: Introductionmentioning

confidence: 99%

Association of rs4646903 and rs1048943 CYP1A1 estrogen-metabolizing gene polymorphisms with estrogen receptor-positive breast cancer in Kenyan women

Murithi

Nyanjom

Mobegi

et al. 2023

ARCH BIOL SCI BELGRA

Breast cancer is the most prevalent neoplasm and the second leading cause of death among females in Kenya. Estrogen and its metabolites are known risk factors for breast cancer. Polymorphisms in these genes and breast cancer susceptibility are unique among different populations. This study aimed to determine the probable associations between estrogen-metabolizing gene variations and other risk factors for breast cancer risk in Kenyan women. Buffy coat samples were obtained from patients diagnosed with estrogen receptor-positive breast cancer, benign breast disease, and healthy volunteers. Genotyping of target polymorphisms was conducted using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. The rs4646903 variant genotype CC was associated with breast cancer in the case-control model (P=0.001); the heterozygous genotype TC (P=0.01) and the luminal B molecular subtype (P=0.02) showed increased odds of late-stage breast cancer. The rs1048943 variant genotype GG was associated with breast cancer in the case-benign model (P=0.04), whereas CG was associated with breast cancer in the case-control model (P=0.02). These findings imply that the rs4646903 and rs1048943 variant genotypes are involved in breast cancer risk in Kenyan women. Hence, they may be explored further as potential markers for the disease.

“…In females, breast cancer is the largest cause of death It can be initiated regardless of age, ethnicity, socioeconomic condition and geographical location. Studies indicated that the burden of breast cancer globally would be more than 2 million by 2030 (Heitz et al, 2018;Francis et al, 2019). It has several types depending upon its localization and spread.…”

Section: Introductionmentioning

confidence: 99%

Mutation Profiling of PI3K/AKT1/MTOR Pathway Genes in Breast Cancer Patients of Pakistan

Iqbal,

Shakoori,

Muneer

et al. 2023

PJZ