A mechanism by which progesterone promotes estrogen receptor (ER)- and progesterone receptor (PR)-positive breast cancers to become more stem-like, aggressive and resistant to standard endocrine and chemotherapies is described by researchers at the University of Colorado, Denver. Their results indicate that one particular microRNA, miR-29, may represent a druggable target for helping to prevent the cancer from converting into a treatment-resistant phenotype.
The expansion of hormone receptor-positive breast cancer cells is associated with loss of ER and PR expression, and upregulation of the tumor-initiating marker CD44 and progenitor marker cytokeratin 5 (CK5). However, the mechanisms underlying this hormone-stimulated reprogramming have remained mainly elusive, report Diana Ciettelly, Ph.D., Jennifer Richer, Ph.D., and colleagues.
Looking more closely at the role of miRNAs in progesterone-mediated dedifferentiation and expansion of tumor cells, the researchers found that the hormone acts to downregulate miR-29 family members, particularly in the CD44+ cell population. Their studies showed that downregulation of miR-29 enhanced the expansion of CK5+ and CD44+ cells in response to progestins, resulting in increased stem-like properties both in vitro and in vivo.
“The reason we were looking into the possible role of microRNAs in the dedifferentiation of breast cancer cells into this aggressive, chemo-resistant phenotype is that microRNAs tend to be good, druggable targets,” Dr. Cittelly states. “Because one microRNA may regulate many genes involved in a cancerous signaling pathway, we hoped to find one target with many beneficial effects.”
Having implicated miR-29 in this process, the team carried out additional experiments suggesting that miR-29 directly targets the transcription factor Krüppel-like factor 4 (KLF4), which is involved in reprogramming differentiated cells back into pluripotent stem cells and the maintenance of breast cancer stem cells.
The researchers report their findings in Oncogene, in a paper titled “Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4.” Dr. Cittelly hopes the new insights will help lead to new anticancer treatment approaches. “We can manipulate this miR-29 in cell lines, and we hope technology isn’t too far in the future that will allow us to deliver miR-29 in human cancers as well.”