SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study

Abstract

Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.

Assessment of the Selenoprotein M (SELM) over-expression on human hepatocellular carcinoma tissues by immunohistochemistry

“… 19 Moreover, SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher native american ancestry and GPX1 , GPX3 , and SELS with Estrogen Receptor-/Progesterone Receptor+ status. 20 Lower SEPP1 concentrations resulted to correlate also with higher tumor grade and tumor stage in patients with renal cancer. 21 However, data from case-control studies suggested that a variant in GPX1 influenced the effect of Se status on prostate, breast and lung cancer risk, whereas variants in GPX4 , SEPP1 and SELS may influence the risk of colorectal cancer.…”

Low spinophilin expression enhances aggressive biological behavior of breast cancer

“…SERPINB5 (serpin peptidase inhibitor, clade B (ovalbumin), member 5) is implicated as a tumor suppressor which is absent in breast and prostate cancer [ 40 ] and has also a possible causal role in metastasis [ 41 ]. SEPP1 (selenoprotein P, plasma, 1) has been associated with breast cancer risk among women with higher Native American ancestry [ 42 ].…”

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

“…Moreover, resistant cells showed higher expression of selenoprotein P plasma 1 (SEPP1) and nicotinamide nucleotide transhydrogenase (NNT) (Fig. 4), both recognized as antioxidant enzymes through their direct detoxifying activity (in the case of SEPP1) or by generating nicotinamide adenine dinucleotide phosphate (NADPH), a critical modulator of the cell redox state (in the case of NNT) (30,40,68,76). BT474 cells also present higher expression of the aldehyde dehydrogenase 7 family, member A1 (ALD-H7A1), and aldehyde dehydrogenase 3 family, member B2 (ALDH3B2), both involved in the detoxification of aldehydes derived from lipid peroxidation, an effect of cellular oxidative stress (7,27).…”