Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness Gary Xiao, Ph.D. Professor and Director School of Pharmaceutical Science & Technology Dalian University of Technology Dalian, China

Each day: 1,500 people in the U.S. will die of cancer Each year: 1,220,100 people in the U.S. will be diagnosed with cancer Ultimately: One in four people in the U.S. will die of cancer Cancer Statistics Leading Cancer Types: Breast: 16.3% of all cancer cases with a 40% increase since % of all cancer deaths Lung: 13.2% of all cancer cases with a 1.6 percent per year decline from 1992 to % of all cancer deaths Prostate: 14.8% of all cancer cases with an average 5.7 % per year decline from 1992 to % of all cancer deaths Colorectal: 11.6% of all cancer cases with sharply different rates among racial and ethnic groups 10.5% of all cancer deaths

Leading New Cancer Cases and Deaths – 2013 Estimates ?

Challenge for administration of Breast Cancer Challenge in the treatment of breast cancer: Recurrence and relapse, which was initiated and maintained by remaining cancer stem cells (CSCs) from either residual tumors or those with intrinsic resistance to adjuvant therapy.

Breast Cancer Stem Cells (BCSCs) The breast CD44 + cells are basal-like, similar to normal breast stem cells; CD24 + cells express markers of luminal differentiation. CD44 + /CD24 - breast cancer cells  preferentially survive treatment compared to the more differentiated cancer cells. Thus, being used as therapeutic target cells.

6 Biogenesis of microRNAs

BenignDCISIDC * Regulatory Role of microRNAs in Tumoregensis ? Zhao et al., 2011 Breast Cancer Res Trt

CSC Specific therapy Tumor regression Convensional cancer therapy Tumor relapse miR-34a: CSC specific therapy? miR-34a:  CSC self-renewal  apoptosis? X

Reciprocal endogenous expression of miR-34a and SIRT1 in CD44+/CD24− BCSCs

Down-regulation of SIRT1 and over-expression of miR- 34a inhibit cell growth and colony formation abilities

Endogenous expression of SIRT1 in CD44+/CD24− BCSCs

Inhibitory effect of miR-34a-SIRT1 axis on cell proliferative potential in MCF-7 cells

Repression of miR-34a-SIRT1 axis on the proportion of CD44+/CD24- BCSCs

Repression of miR-34a-SIRT1 axis mammosphere formation capacity

miR-34a suppressed expression of stem cell markers

Alteration of miR-34a-SIRT1 axis supressed Nanog

Modulation of miR-34a- SIRT1 axis enhanced MCF-7 cell apoptosis

MiR-34a over-expression or silenced SIRT1 inhibited tumor growth in vivo.

Subcutaneous tumor regeneration from MCF-7 cells infected with lentivirus-miR-34a(miR-34a) or shRNA- SIRT1(shRNA-SIRT1)

qRT-PCR analyses of miR-34a expression in each group of xenograft tissues

Protein levels of SIRT1, and ALDH1 in each group of mice tumors

miR-34a caused breast cancer stem cell apoptosis through its target genes

Acknowledgements This research is supported by Chinese NSFC ( ) DLUT seed grant ( ) School of Pharmaceutical Science & Technology Dalian University of Technology Dalian, China