AsianScientist (Jun. 2, 2015) – A cluster of non-coding ribonucleic acids (ncRNA) has been implicated in endocrine therapy resistant breast cancer, according to a study published in Nature Communications. The study also found that a polyphenol known as resveratrol was able to repress these ncRNAs, thereby inhibiting the growth of drug-resistant breast cancer cells.
revealed that a cluster of defined, non-coding ribonucleic acids (ncRNAs) are mechanistically involved in endocrine therapy resistance in human breast cancer cells. Furthermore, resveratrol, a kind of polyphenol, was found to repress these RNAs and inhibit the proliferative activity of breast cancer cells which had acquired resistance. The work has been published in Nature Communications.
Breast cancer is one of the most common types of cancer in women. In recent years, both early diagnosis and emerging therapies have been improved by the progress of medical technology. However, the fact that many patients suffer from metastasis and later recurrence of this disease is an important issue.
The keys to help understand the nature of breast cancer cells are estrogens and estrogen receptors. These molecules together present a “lock-and-key” theory for breast cancer therapy. About 60-70 percent of breast cancers are estrogen receptor-α (ER)-positive and highly depend on estrogen for cellular growth and survival. Thus, endocrine therapies, such as those using an aromatase inhibitor, block estrogen action and are clinically the most effective for ER-positive breast cancers.
Unfortunately, these treatments are often followed by disease recurrence because most breast tumors are initially responsive to these therapies but then develop resistances through unknown mechanisms. Cancer recurrence is further associated with metastasis and invasion. For this reason, identification of the mechanism of therapy resistance has been strongly anticipated.
To analyze the cancer cell adaptation process, a research group led by Professor Mitsuyoshi Nakao, director of the Institute of Molecular Embryology and Genetics in Kumamoto University and Associate Professor Noriko Saitoh used the human breast cancer cell line MCF7. These cells are ER-positive and can continue growth even after long term estrogen deprivation (LTED), similar to cancer cells that are resistant to endocrine therapy.
They showed that the expression of the ER gene (ESR1) was up-regulated during adaptation in the LTED cells in a manner that was dependent on novel ncRNAs produced from the ESR1 gene locus.
Fluorescence in situ hybridization (FISH) analyses showed that these ncRNAs, termed Eleanors (ESR1 locus enhancing and activating non-coding RNAs), were localized at the site of actively transcribed ESR1 locus, resulting in the formation of distinct RNA foci in the nucleus.
It was further revealed that resveratrol, a kind of polyphenol, exerted a repressive effect on the Eleanors via the ER and down-regulated the ESR1 gene which inhibited the proliferative activity of the LTED cells.
These findings uncovered the molecular basis for endocrine therapy-resistant breast cancer, showing the essential role of a new type of ncRNA-mediated regulation of the ESR1 gene locus.
In summary, Eleanors ncRNAs are actively involved in the epigenetic adaptation of ER-positive breast cancer cells via high expression of the ESR1 gene. These findings highlight the ncRNA-mediated mechanisms in cancer cell adaptation, which may be diagnostic and therapeutic targets for endocrine therapy-resistant breast cancer.
The article can be found at: Tomita et al. (2015) A Cluster Of Noncoding RNAs Activates The ESR1 Locus During Breast Cancer Adaptation.
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Source: Kumamoto University; Photo: Caroline/Flickr/CC.
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