Downregulation of Bmi1 in breast cancer stem cells suppresses tumor growth and proliferation

Abstract

Targeting cancer stem cells during initial treatment is important to reduce incidence of recurrent disease. Bmi1 has been associated with cancer stem cell self-renewal and aggressive disease. The purpose of this study was to determine the effects of downregulation of Bmi1 in breast cancer stem cells in order to target and eliminate the stem cell population in the tumor mass. Bmi1 was downregulated using two approaches in the mouse breast cancer stem cell line FMMC 419II—a small molecule inhibitor (PTC 209) and stable transfection with a Bmi1 shRNA plasmid. The functional effect of Bmi1 downregulation was tested in vitro and in vivo. Each approach led to decreased Bmi1 expression that correlated with an inhibition of cancer stem cell properties in vitro including cell cycle arrest and reduced mammosphere forming potential, and a decrease in tumor mass in vivo after either intra-tumoral or systemic nanoparticle-targeted delivery of anti-Bmi1. These results show that inhibiting Bmi1 expression in breast cancer stem cells could be important for the complete elimination of tumor and potentially preventing disease relapse.

CUL4B regulates cancer stem‐like traits of prostate cancer cells by targeting BMI1 via miR200b/c

“…Mechanistically, CUL4B promotes BMI1 expression and upregulates BMI1 via epigenetically repressing miR200b/c. BMI1, a member of the PcG protein, has been shown to play an important role in epigenetic regulation of cell differentiation and proliferation, as well as in the self‐renewal of CSCs . So far, multiple studies have demonstrated an oncogenic role of BMI1 in PCa progression .…”

“…BMI1, a member of the PcG protein, has been shown to play an important role in epigenetic regulation of cell differentiation and proliferation, as well as in the self-renewal of CSCs. 41 So far, multiple studies have demonstrated an oncogenic role of BMI1 in PCa progression. 14,42 BMI1 expression level was associated with invasion, metastasis, drug resistance, and poor prognosis of PCa.…”

Update on the role and therapeutic potential of polycomb repressive complexes in (biliary tract) cancer

“…Looking at the expression of CD49f as an established surface marker of breast cancer CSC, in vitro and in vivo experiments demonstrated that the CD49f-positive subpopulation of breast cancer cells was reduced after PTC-209 incubation. Additionally, PTC-209 markedly reduced size and weight of tumors in vivo [9].…”

“…In the initial study regarding PTC-209 by Kreso and coworkers, the authors described a profound effect of PTC-209 on the CSC fraction of colorectal cancer [5]. Since then, various studies investigated the role of BMI1 and/or the effect of BMI1 inhibition on the CSC and demonstrated a connection in glioma, hepatocellular carcinoma, and breast cancer [9,13,14]. Albeit rarely investigated, the current literature suggests a contribution of CSCs also for BTC [15].…”

“…Furthermore, PTC-209 induced expression of the tumor suppressors p16INK4a, p21 and p53. Srinivasan et al also investigated the effect of PTC-209 in breast cancer using a CSC cell model [9]. Again, PTC-209 caused accumulation of cells in the G1 phase of the cell cycle as well as reduction of quantity and size of tumor spheres.…”