title: Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer.
abstract: Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Pandey
authors.forename: F
authors.initials: F
authors.lastname: Xing
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.forename: M
authors.initials: M
authors.lastname: Watabe
authors.forename: S K
authors.initials: SK
authors.lastname: Pai
authors.forename: M
authors.initials: M
authors.lastname: Iiizumi-Gairani
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: S
authors.initials: S
authors.lastname: Hirota
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Mo
authors.forename: K
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D000077185:Resveratrol; D013234:Stem Cells / Q000473:pathology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D013267:Stilbenes; D023041:Xenograft Model Antitumor Assays
chemical_list: C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D013267:Stilbenes; D000077185:Resveratrol