Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer

• Published in: Oncogene Vol. 32; no. 42; pp. 5111 - 5122
• Main Authors: Pandey, P R, Xing, F, Sharma, S, Watabe, M, Pai, S K, Iiizumi-Gairani, M, Fukuda, K, Hirota, S, Mo, Y-Y, Watabe, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.10.2013; Nature Publishing Group
• Subjects: 631/67/1059/99; 631/67/71; 631/80/82/23; 692/699/67/1347; Animals; Apoptosis; Apoptosis - drug effects; Biochemistry; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer; Carcinoma, Ductal; Carcinoma, Intraductal, Noninfiltrating - metabolism; Carcinoma, Intraductal, Noninfiltrating - pathology; Carcinoma, Intraductal, Noninfiltrating - prevention & control; Care and treatment; CD44 antigen; Cell Biology; Cell culture; Cell death; Cell Line, Tumor; Cell Proliferation; Cell surface; Cell Survival; Ectopic expression; Fatty acids; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Human Genetics; Humans; Internal Medicine; Lipogenesis; Lipogenesis - drug effects; Lipogenesis - genetics; Medicine; Medicine & Public Health; Mice; Mice, Nude; Oncology; original-article; Polyphenols; Resveratrol; Stem cells; Stem Cells - pathology; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Stilbenes; Surface markers; Synthesis; Testing; Tumors; Xenograft Model Antitumor Assays; breast cancer; apoptosis; lipogenesis; stem-like cells; ductal carcinoma; resveratrol
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.519

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.