Upregulation of miR-195 increases the sensitivity of breast cancer cells to Adriamycin treatment through inhibition of Raf-1

Oncol Rep. 2013 Aug;30(2):877-89. doi: 10.3892/or.2013.2532. Epub 2013 Jun 11.


Chemotherapy is an important option for the treatment of advanced breast cancer, but multidrug resistance is one of the major obstacles in the clinical control of breast cancer. The present study investigated the effects of the miR‑195-led gene pathway in the sensitization of breast cancer cells to treatment with the chemotherapeutic drug Adriamycin. Breast cancer cell lines and tissue specimens (obtained from chemotherapy-sensitive or resistant patients) as well as a normal breast cell line were used to assess expression of miR-195, Raf-1, Bcl-2 and P-glycoprotein mRNA and/or mRNA. miR-195 mimics, inhibitor and Raf-1 siRNA were used to transfect breast cancer MCF-7 and MCF-7/ADR cells (an Adriamycin-resistant MCF-7 subline) for cell viability, apoptosis and gene expression analysis. The data showed that miR-195 expression was low in breast cancer cells and multidrug-resistant breast cancer tissues, which was associated with reduced Raf-1 expression in vitro and ex vivo. Induction of miR-195 expression promoted tumor cell apoptosis and inhibited breast cancer cell viability, but induced the sensitivity of breast cancer cells to Adriamycin treatment and was associated with inhibition of Raf-1 expression in breast cancer cells. Moreover, knockdown of Raf-1 expression had similar effects of miR-195 mimics on breast cancer cells, both of which were able to suppress Bcl-2 and P-glycoprotein expression in breast cancer cells. The data from the current study demonstrated that expression of miR-195 was inversely associated with Raf-1 expression in breast cancer cell lines and tissue specimens, and that Raf-1 is the target gene of miR-195. Thus, expression of miR-195 or knockdown of Raf-1 can similarly reduce tumor cell survival but increase apoptosis through downregulation of Raf-1 and Bcl-2 and P-glycoprotein expression. In conclusion, this gene pathway mediated the sensitivity of breast cancer cells to Adriamycin treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Doxorubicin / pharmacology*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Humans
  • MCF-7 Cells
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-raf / biosynthesis
  • Proto-Oncogene Proteins c-raf / deficiency
  • Proto-Oncogene Proteins c-raf / genetics
  • RNA, Messenger / genetics
  • Up-Regulation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • MIRN195 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Doxorubicin
  • Proto-Oncogene Proteins c-raf