Breast Cancer-Initiating Cells: Insights into Novel Treatment Strategies

Abstract

There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24−/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways.

MiRNA-513a-5p inhibits progesterone receptor expression and constitutes a risk factor for breast cancer: the hOrmone and Diet in the ETiology of breast cancer prospective study

“…It is worth noting that the pathways identified by the three differentially upregulated miRNAs were very similar and related to both breast cancer and more general cancer development (e.g. ErbB, mTOR, TGFb and Wnt pathways) (31)(32)(33)(34)(35). We then also observed that the three miRNAs targeted pathways also related to insulin and other endocrine/metabolic pathways recognized in the ORDET cohort, as well as in other studies as pathways involved in breast cancer development (10,32,36).…”

Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells

“…Fluorescence-activated cell sorting analysis (FACS) and/or magnetic-activated cell sorting analysis (MACS) are designed to isolate CSCs expressing specific biomarkers, such as CD44 + , CD24 − , EpCAM + , and ALDH hi , etc. [ 45 , 46 ]. The second strategy is to utilize biofunctions of CSCs.…”

Targeting aberrant expression of Notch‐1 in ALDH+ cancer stem cells in breast cancer

“…Of these, 1–2% are breast cancer stem cells (BCSCs) and are believed to initiate and promote tumorigenesis . There is increasing evidence that these small fractions of BCSCs are responsible for metastasis, tumor recurrence, and resistance to chemotherapeutic agents . Previously, we and others reported that chemotherapeutic agents such as docetaxel, doxorubicin, or 5‐flurouracil (5‐FU) fail to inhibit the growth of BCSCs or to preferentially target and kill differentiated breast cancer cells .…”