Scientists have found for the first time that the small nucleoli RNA SNORD33 has a predictive effect on platinum-based treatment options for triple-negative breast cancer

Schematic diagram of the mechanism by which SNORD33 regulates platinum sensitivity in triple-negative breast cancer cells (courtesy of respondents)

Recently, Molecular Tumor published a research result online by Professor Wang Biyun and Hu Xichun of the Affiliated Cancer Hospital of Fudan University and Chen Shu, a researcher at the School of Basic Medical Sciences of Fudan University, on the prediction of the effect of chemotherapy for triple-negative breast cancer. The study found for the first time that the expression level of triple-negative breast cancer patients receiving platinum-containing drug regimens but with different efficacy showed significant differences in expression levels, which can be used as a marker to predict the effect of this treatment regimen.

In addition, the research team also combined the tumor metastasis to draw a line chart that can predict the survival of patients with metastatic triple-negative breast cancer with platinum regimens.

No valid markers have been found

Triple-negative breast cancer accounts for about 15% of all breast cancers, and is recognized as the "most difficult to treat" breast cancer because of its high degree of malignancy, lack of precise therapeutic targets, high risk of recurrence and metastasis, and low overall survival rate compared with other breast cancer subtypes.

Platinum chemotherapy drugs are a commonly used regimen in the treatment of triple-negative breast cancer, which mainly play an anti-cancer role by influencing the synthesis and repair of cancer cell genes. Clinically, many patients require platinum-based treatment. However, there are still some patients with triple-negative breast cancer who do not respond to platinum-based therapy.

Wang Biyun said that if the platinum drug resistance in triple-negative breast cancer patients can be screened in advance, it can be "classified and treated", so that the "predicted drug resistance" population avoids "ineffective drugs", thereby improving the treatment effect of the platinum program, achieving more accurate treatment of the patient group, and prolonging the survival time of patients.

However, the medical community has not yet found a biomarker that can accurately predict the efficacy of platinum drug regimens for triple-negative breast cancer.

The predictive effects of SNORD33 were discovered

It is understood that small nucleolid ribonucleic acid (snoRNA) is a kind of cytogenetic material, which plays a role in promoting cancer or inhibiting cancer in a variety of tumors, and this genetic material has a certain distribution in body fluids such as plasma, so it is regarded as a potential biomarker for liquid biopsy.

In the previous study, the research team found that the expression level of small nucleoli RNA SNORD33 was significantly lower in patients resistant to cisplatin therapy regimen for triple-negative breast cancer through in-depth detection of second-generation gene sequencing technology. In addition, the downregulation of SNORD33 promoted resistance to cisplatin in triple-negative breast cancer cells in vitro.

Can SNORD33 be used as a predictive marker for the long-explored platinum regimen for triple-negative breast cancer? To this end, the research team based on plasma samples from 209 patients with metastatic triple-negative breast cancer who received platinum-containing regimens in the first line, and found that patients with low levels of SNORD33 in plasma had significantly lower survival times than those in the SNORD33 high-level group.

Studies have confirmed that plasma SNORD33 is an independent predictor of survival in patients treated with triple-negative breast cancer using a platinum-containing regimen. In addition, in a sample of 45 patients treated with a first-line non-platinum regimen, plasma SNORD33 levels were not significantly correlated with survival, suggesting the specificity of SNORD33 for the prediction of platinum efficacy.

In order to better predict the efficacy of platinum treatment for triple-negative breast cancer, a line chart that can predict the survival time of patients with platinum-containing first-line treatment of metastatic breast cancer was also prepared by combining the three important indicators of baseline liver metastases, the number of metastatic foci and the level of SNORD33 in plasma.

Hu Xichun said that through the analysis of the line chart, individualized calculations can be performed on each patient, and then the probability of progress in different months can be obtained. That is, the probability of patient survival using platinum-containing protocols is judged by simple calculation at baseline, which makes up for the relatively "slightly rough" shortcomings of prognosis judgment only by the level of SNORD33 expression, and further improves the feasibility of plasma SNORD33 as a molecular target for platinum drug prediction.

Constant search for mechanisms of drug resistance

Subsequently, the research team further explored the role of SNORD33 in the resistance of platinum regimens in triple-negative breast cancer, in order to further clarify the mechanism of this substance regulating platinum sensitivity in triple-negative breast cancer and provide a reference for subsequent treatment strategies.

Using SNORD33-binding protein profiling technology, it was found that SNORD33 was bound to the methylation-binding protein MeCP2. The data showed that the downregulation of SNORD33 levels would increase the binding of MeCP2 to the methylated region of the downstream target gene promoter, release the transcriptional inhibition activity of MeCP2, and further inhibit the expression of apoptotic-related genes including GADD45α, MYOD1, FOXF1, CDKL5, CLDN6, resulting in a decrease in apoptosis, thereby increasing the resistance of triple-negative breast cancer cells to platinum.

"The follow-up results further reveal the mechanism of SNORD33 regulating platinum resistance in triple-negative breast cancer," Wang Said, "which also inspires us to start from this regulatory process and carry out deeper research to improve the treatment effect of platinum drugs and benefit more triple-negative breast cancer patients." (Zhang Siwei, Huang Xin)

Related thesis information: https://doi.org/10.1186/s12943-022-01504-0

Source: China Science Daily