PONE-D-21-23611High RRM2 expression has poor overall survival in specific types of breast cancerPLOS ONE

Dear Dr. Wang,

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript entitled “High RRM2 expression has poor overall survival in specific types of breast cancer” by Shi et al, evaluates the role of RRM2 as a prognostic biomarker in breast cancer and attempts to relate the expression level of RRM2 in the METABRIC database with the overall survival of breast cancer patients. Although the authors claim that RRM2 has not been studied in detail in breast cancer, more comprehensive studies such as “Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers” already exist. There is no mention of this study or any other existing literature on breast cancer. This substantially undermines the novelty of this study. Further, there are other concerns.

1.In the results section, more explanation on the type of correlation of RRM2 expression with clinical features is needed. Similarly, the authors need to explain the results of Figure 2, detailing the trends that are observed.

2.The figure legend in Figure 4B is misrepresented. Figure 4B shows that Stage 1 breast cancer patients had the best overall survival and stage 4 the worst and doesn’t relate the expression of RRM2 to poor overall survival in stage 1 and stage 2 breast cancer patients.

3.The manuscript provides no explanation for why high expression of RRM2 has poor overall survival in patients with Luminal A subtype and Normal-like subtype breast cancers.

4.The manuscript needs to be corrected for grammar and flow. For example, the sentences in lines 103 to 105 need to be simplified. Grammatical errors and language inconsistencies impair flow and render reading the manuscript a tedious task.

5.The last line of materials and methods in the abstract “Finally, using GSEA to study the differentially expressed RRM2 may affect the related pathways of breast cancer progression” needs to be rephrased to increase comprehension.

Unless the authors can support their findings with some experimental data, this manuscript is not suitable for publication.

Reviewer #2: This manuscript demonstrates the role of RRM2 in breast cancer. Authors have shown that higher RRM2 of RRM2 is associated with a worse prognosis in breast cancer patients. They utilized publically available datasets such as KM plotters via utilizing univariate or multivariate analyses and GSEA analysis to show that RRM2 is indeed an important molecule for breast cancer progression and its higher expression is associated with ErbB and other cancer-associated signaling pathways. Overall, these studies suggest that RRM2 could be used as a prognostic factor for breast cancer patients. Although the findings are interesting and well organized, these studies are lacking some further details. RRM2 has been associated with drug resistance in other cancer types. Is RRM2 involved with chemoresistance in several breast cancer subtypes? It is also important to know if RRM2 is associated with distant metastasis-free survival. In addition, this reviewer would like to know if the gene expression data of RRM2 is also correlated with the proteomic data or protein atlas data.

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Reviewer #1: No

Reviewer #2: No

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High RRM2 expression has poor prognosis in specific types of breast cancer

PONE-D-21-23611R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Surinder K. Batra

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: I appreciate authors for including new data to answer my queries. After revision, this manuscript is improved significantly.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No