Dysregulation of the miR-34a-SIRT1 axis inhibits breast

cancer stemness

Gary Xiao, Ph.D.Professor and Director

School of Pharmaceutical Science & TechnologyDalian University of Technology

Dalian, China2015. 3.16.

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 1973 7.8% of all cancer deaths

Lung: 13.2% of all cancer cases with a 1.6 percent per year decline from 1992 to 1998 29% of all cancer deaths

Prostate: 14.8% of all cancer cases with an average 5.7 % per year decline from 1992 to 1998 5.9% 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

www.seer.cancer.gov       www.cdc.gov/cancer/    www.naaccr.org/

Leading New Cancer Cases and Deaths – 2013 Estimates

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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.

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Biogenesis of microRNAs

Benign DCIS IDC

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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 cellproliferative potential in MCF-7 cells

Inhibitory effect of miR-34a-SIRT1 axis on cellproliferative 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)

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

AcknowledgementsThis research is supported by

Chinese NSFC (8120734)DLUT seed grant (1003852014)

School of Pharmaceutical Science & TechnologyDalian University of TechnologyDalian, China