Abstract
The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0.043, P=0.002, P=0.008, respectively), and the C allele carriers had a 1.224-fold significantly increased risk of developing BC (P= 0.003). Moreover, a higher frequency of AKT rs2494752 AG genotype was observed among cases (P=0.045). Individuals harboring rs2494752 AG/AA genotype had a vital increased susceptibility to BC in the dominant model (P=0.039). More importantly, AKT1 rs2494752 GG genotype showed significantly rates of response to NCT chemotherapy (P=0.048). Furthermore, AKT1 rs2494752 AG genotype carriers showed significantly shorter DFS time, and GG genotype as the independent prognostic factor (DFS: adjusted HR=1.523, 95% CI=1.012-2.293, P=0.044; OS: adjusted HR=2.321, 95% CI=1.281-4.204, P=0.005). Moreover, MDR analysis consistently revealed that the combination of 3 selected SNPs and 7 known risk factors represented the best model to predicting BC prognosis. The luciferase assay showed that the G allele of rs2494752 significantly increased AKT1 promoter activity. These results suggest that PTEN rs701848 and AKT1 rs2494752 polymorphisms might be a candidate pharmacogenomic factor to assess the susceptibility of BC and response and prognosis prediction for interindividualized CE(A)F chemotherapy in BC patients.
Highlights
Breast cancer (BC) is the leading cause of cancerrelated death in women aged 20 to 59 years, with an estimated 231,840 new cases of invasive BC among women in the USA during 2015 [1, 2]
The PI3K/PTEN/Serine/threonine Kinase (AKT) pathway play a critical role in balancing cell growth and death
Thereafter, we further investigated the effect of the combined genotypes of PTEN rs701848 and AKT1 rs2494752 on the BC risk, and found 6.170fold increased risk in rs701848CC and rs2494752GG genotypes
Summary
Breast cancer (BC) is the leading cause of cancerrelated death in women aged 20 to 59 years, with an estimated 231,840 new cases of invasive BC among women in the USA during 2015 [1, 2]. BC alone is expected to account for 29% of all new cancers in women [3]. Observational studies have revealed that breast cancer is a complex disease caused by environmental exposures and genetic factors such as germline mutations in a multi-step process of breast carcinogenesis. Recent numerous genomic studies reported that breast cancer consists of a complex biological process with patient-specific genetic variations [4]. Improving the treatment efficacy and prognosis prediction www.impactjournals.com/oncotarget requires a better understanding of the genetic risk factors that involve in the breast cancer carcinogenesis
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