Therapeutic targeting of metastatic breast cancer still remains a challenge as the tumor cells are highly heterogenous and exploit multiple pathways for their growth and metastatic spread that cannot always be targete...Therapeutic targeting of metastatic breast cancer still remains a challenge as the tumor cells are highly heterogenous and exploit multiple pathways for their growth and metastatic spread that cannot always be targeted by a single-agent monotherapy regimen.Therefore,a rational approach through simultaneous targeting of several pathways may provide a better anti-cancer therapeutic effect We tested this hypothesis using a combination of two nutraceutical agents S-adenosylmethionine(SAM)and Vitamin D(Vit.D)prohormone[25-hydroxyvitamin D;/25(OH)D,]that are individually known to exert distinct changes in the expression of genes involved in tumor growth and metastasis.Our results show that both SAM and 25(OH)D monotherapy significantly reduced proliferation and clonogenic survival of a panel of breast cancer cell lines in vitro and inhibited tumor growth,lung metastasis,and breast tumor cell colonization to the skeleton in vivo.However,these effects were significantly more pronounced in the combination setting.RNA-Sequencing revealed that the transcriptomic footprint on key cancer-related signaling pathways is broader in the combination setting than any of the monotherapies.Furthermore,comparison of the differentially expressed genes from our transcriptome analyses with publicly available cancer-related dataset demonstrated that the combination treatment upregulates genes from immune-related pathways that are otherwise downregulated in bone metastasis in vivo.Since SAM and Vit.D are both approved nutraceuticals with known safety profiles,this combination treatment may serve as a novel strategy to reduce breast cancer-associated morbidity and mortality。展开更多
The impact of early physical and social environments on life-long phenotypes is well known. Moreover, we have documented evidence for gene-environment interactions where identical gene variants are associated with dif...The impact of early physical and social environments on life-long phenotypes is well known. Moreover, we have documented evidence for gene-environment interactions where identical gene variants are associated with different phenotypes that are dependent on early life adversity. What are the mechanisms that embed these early life experiences in the genome？ DNA methylation is an enzymatically- catalyzed modification of DNA that serves as a mechanism by which similar sequences acquire cell type identity during cellular differentiation and embryogenesis in the same individual. The hypothesis that will be discussed here proposes that the same mechanism confers environmental-exposure specific identity upon DNA providing a mechanism for embedding environmental experiences in the genome, thus affecting long-term phenotypes. Particularly important is the environment early in life including both the prenatal and postnatal social environments.展开更多
文摘Therapeutic targeting of metastatic breast cancer still remains a challenge as the tumor cells are highly heterogenous and exploit multiple pathways for their growth and metastatic spread that cannot always be targeted by a single-agent monotherapy regimen.Therefore,a rational approach through simultaneous targeting of several pathways may provide a better anti-cancer therapeutic effect We tested this hypothesis using a combination of two nutraceutical agents S-adenosylmethionine(SAM)and Vitamin D(Vit.D)prohormone[25-hydroxyvitamin D;/25(OH)D,]that are individually known to exert distinct changes in the expression of genes involved in tumor growth and metastasis.Our results show that both SAM and 25(OH)D monotherapy significantly reduced proliferation and clonogenic survival of a panel of breast cancer cell lines in vitro and inhibited tumor growth,lung metastasis,and breast tumor cell colonization to the skeleton in vivo.However,these effects were significantly more pronounced in the combination setting.RNA-Sequencing revealed that the transcriptomic footprint on key cancer-related signaling pathways is broader in the combination setting than any of the monotherapies.Furthermore,comparison of the differentially expressed genes from our transcriptome analyses with publicly available cancer-related dataset demonstrated that the combination treatment upregulates genes from immune-related pathways that are otherwise downregulated in bone metastasis in vivo.Since SAM and Vit.D are both approved nutraceuticals with known safety profiles,this combination treatment may serve as a novel strategy to reduce breast cancer-associated morbidity and mortality。
基金supported by a grant from the Canadian Institute of Health Research to M.S. M.Ssupported by the Sackler program in epigenetics and psychobiology at McGill University,Canada
文摘The impact of early physical and social environments on life-long phenotypes is well known. Moreover, we have documented evidence for gene-environment interactions where identical gene variants are associated with different phenotypes that are dependent on early life adversity. What are the mechanisms that embed these early life experiences in the genome？ DNA methylation is an enzymatically- catalyzed modification of DNA that serves as a mechanism by which similar sequences acquire cell type identity during cellular differentiation and embryogenesis in the same individual. The hypothesis that will be discussed here proposes that the same mechanism confers environmental-exposure specific identity upon DNA providing a mechanism for embedding environmental experiences in the genome, thus affecting long-term phenotypes. Particularly important is the environment early in life including both the prenatal and postnatal social environments.
