Abstract 5169: Roles of lipogenesis in cancer stem-like cells at early stage of breast cancer
Authors: Pandey Puspa Raj , Xing Fei , Kobayashi Aya , Gairani Megumi , Watabe Misako , Pai Sudha K. , Fukuda Koji , Hirota Shigeru , Modur Vishnu , Sharma Sambad , Watabe Kounosuke 
Published: August 2012

Abstract
Ductal carcinoma in situ (DCIS) is considered an early stage of breast cancer and it is the precursor of invasive breast carcinoma. However, the transition from normal breast epithelial cells to DCIS is still not clearly elucidated. In order to determine the role of lipogenesis in normal to DCIS transition, we investigated the roles of SREBP1, a major transcription regulator of lipogenesis and its downstream lipogenic genes such as ACLY, ACC1 and FAS, by isolating cancer stem-like cells (CSCs) from DCIS.com cell line which forms typical DCIS lesions in animals by using the well-established cell surface markers, CD24−/CD44+/ESA+. We found that lipid synthesis was significantly upregulated in CSCs from DCIS.com in contrast to the corresponding population from normal breast epithelial cells (MCF10A). Furthermore, we found that this elevation of lipogenesis is indeed caused by the overexpression of SREBP1 which co-ordinately induces the overexpression of the downstream lipogenic genes. The CSCs obtained from DCIS.com were also found to be more tumorigenic than the parental cells as shown by the limiting dilution analysis. To determine the role of elevated level of SREBP1 and lipogenesis in the transition of normal breast epithelial cells to DCIS phenotype, we overexpressed SREBP1 in MCF10A and examined the transforming properties. Our in vitro data showed that MCF10A-SREBP1 cells indeed expressed a significantly higher level of SREBP1 and other lipogenic genes and this elevated level of lipogenesis resulted in the increased cell proliferation, increased mammospheres forming ability and enhanced cellular growth in 3D culture. These data suggest that increased lipogenesis in breast CSCs plays critical roles in DCIS formation. We also examined the effects of Resveratrol on CSCs from DCIS.com. Resveratrol significantly reduced the total lipid content by inhibiting SREBP1 and in turn other lipogenic genes and induced a series of pro-apoptotic genes such as DAPK2 and BNIP3 causing the death of CSCs from DCIS. The mammosphere forming ability of CSCs from DCIS was also blocked by Resveratrol. We also observed that Resveratrol indeed significantly suppressed the formation of DCIS by inhibiting lipogenesis and by upregulating DAPK2 and BNIP3 in our animal model of human DCIS. Collectively, our results indicate that lipogenic genes ACLY, ACC-1, FAS and SREBP1 are significantly up regulated in early stage of breast tumorigenesis and they confer proliferative and growth advantages to these cells. Lipogenesis targeting effect of Resveratrol on CSCs from DCIS 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 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5169. doi:1538-7445.AM2012-5169