Abstract 979: Upregulation of lipogenic genes, SREBP-1, ACLY, ACC-1 and FAS, confer proliferation and survival advantages to cancer stem-like cells in ductal carcinoma in situ

Abstract

Abstract Elevated level of lipogenic enzymes and overall lipogenesis have been reported in a wide variety of cancers, and blocking the lipogenic pathway by chemical inhibitors or RNA interference causes tumor cell death by apoptosis. In this study, we investigated the role of lipogenesis in cancer stem-like cells (CSCs) in ductal carcinoma in situ (DCIS) which is considered as an early stage of breast tumorigenesis. CSCs were isolated using cell surface markers (CD24−/CD44+/ESA+) from the MCF10DCIS. Com (DCIS.com) cell line and transplanted into the mammary fat pad of nude mice. The results of our limiting dilution analysis indicate that CSCs had a significantly higher ability of initiating DCIS in the animals. We then examined the expression profile of various lipogenic genes using an expression microarray and found that CSCs from DCIS.com showed significantly higher level of ACLY, ACC-1 and FAS than the normal non-tumorigenic stem-like cells. The result was also confirmed by qRT-PCR and Western blot. We also examined the expression of these genes in clinical specimens of DCIS by immunohistochemistry and found that these genes are indeed significantly upregulated. Furthermore, we found SREBP1, the master regulator of lipogenic genes, was also significantly upregulated in DCIS clinical specimens as well as in DCIS.com cells and inhibition of SREBP1 significantly downregulated the expression of ACLY, ACC-1 and FAS. These results suggest that the lipogenic enzymes play critical roles in initiation and maintenance of DCIS. We then examined the effects of Resveratrol, a natural polyphenol, on CSCs isolated from DCIS.com. We found that Resveratrol reduced the total lipid content of DCIS CSCs by inhibiting lipogenic genes and induced a series of pro-apoptotic genes causing the death of DCIS CSCs. Resveratrol also hindered the stemness of the DCIS CSCs by inhibiting its mammosphere forming ability. When DCIS CSCs was transplanted into mammary fat pad of nude mice followed by treatment with Resveratrol, we observed that Resveratrol indeed significantly suppressed the formation of DCIS by downregulating lipogenic genes and by upregulating pro-apoptotic genes, DAPK2 and BNIP3. Collectively, our results indicate that lipogenic genes ACLY, ACC-1, FAS and SREBP1 are significantly up regulated in DCIS CSCs at an early stage of breast tumorigenesis and they confer proliferative and anti-apoptotic capacity to CSCs. Anti-growth effect of Resveratrol on DCIS CSCs also provides us with a strong rationale to use this agent for chemo-prevention against DCIS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2011-979