Review Reports - Metabolomics and EMT Markers of Breast Cancer: A Crosstalk and Future Perspective

Round 1

Reviewer 1 Report

The review aims to provide overview and future perspectives on metabolic profile of breast cancer regarding EMT markers. Unfortunately, the text as a whole is very difficult to read. Some of the information is merely joined together. A common thread through is missing. Furthermore, the English language is clearly in need of improvement.

Author Response

Response 1: As suggested, authors have revisited the manuscript and revised. As checked through Grammarly software, readability of revised manuscript is now found to be 98%.

Author Response File: Author Response.docx

Reviewer 2 Report

The present paper reviews the metabolic profiling of different breast cancer subtypes with EMT program and markers associated with each subtype. Overall, the authors try to talk about every aspect of cancer, breast cancer, different subtypes of breast cancer, different EMT markers, and different blockers of EMT/MET program in breast cancer, which make the ‘metabolic profiling of breast cancer’ out of focus and the readers are easily get lost. A major revision is required to get rid of the repeated introduction of breast cancer itself and emphasis on the metabolomic part. It seems the authors would more like to discuss the metabolic profiling of breast cancer with different expressions of EMT markers, and the metabolism as regulating of EMT, rather than the metabolic profiling of different subtype of breast cancer, despite they introduced a lot of gene/molecular classification of breast cancer. I would suggest the authors either talk about either the different breast cancer subtypes or different expressions of EMT markers. If so, the title of manuscript should be revised to ensure the accuracy. The author should give a clear summary of related metabolites or metabolic pathway in different breast cancer about either the different breast cancer subtypes or different expressions of EMT markers. More specifical comments are given below:

In the introduction, this review first talk about cancer, then breast cancer, breast cancer gene classification, molecular classification, metastasis of breast cancer, metabolism alterations in cancer. It is recommended we deleted the general introduction of cancer part (line 27-46) and directly talk about epidemiology of breast cancer, breast cancer subtypes, metastasis of breast cancer (EMT, MET), metabolomic approach, why metabolic network can adversely affect the metabolism of breast cancer (metabolic reprogramming). It is recommended to delete Table 1. Because people usually do not put tables in the introduction and the proliferation rate, frequency of incidence, prognosis, too much information in the molecular classification of breast cancer.
In the ‘2. The concept of metabolic rewiring, EMT, MET’, and ‘3. The substantial implication of the EMT process in breast cancer progression’ it is recommended to combined the two parts. Avoid talking too many details in this molecular and cellular mechanisms in the cancer development.
‘4. Current Metabolomic Approaches’, it is recommended that the authors can give a summary of the metabolomics approaches used either in the different breast cancer subtypes or different expressions of EMT markers.
‘The implication of metabolomics in driving the EMT profiling of breast cancer hallmarks. This is the most important part of your manuscript. It is recommended to give a summary of the metabolites altered in the different breast cancer subtypes or different expressions of EMT markers.

Author Response

Reviewer 2:

Comment 1: In the introduction, this review first talks about cancer, then breast cancer, breast cancer gene classification, molecular classification, metastasis of breast cancer, metabolism alterations in cancer. It is recommended we deleted the general introduction of cancer part (line 27-46) and directly talk about epidemiology of breast cancer, breast cancer subtypes, metastasis of breast cancer (EMT, MET), metabolomic approach, why metabolic network can adversely affect the metabolism of breast cancer (metabolic reprogramming). It is recommended to delete Table 1. Because people usually do not put tables in the introduction and the proliferation rate, frequency of incidence, prognosis, too much information in the molecular classification of breast cancer.

Response 1: As suggested, we have made the changes in title and abstract content. We had explained the metabolomics of breast cancer and its correlation on expression of EMT/MET markers. Also, we detailed some of the metabolic inhibitors of EMT program in breast cancer.

As suggested, we have omitted the general introduction of cancer (line 27-46) and initiated the introduction part from epidemiology of breast cancer, why metabolic network can adversely affect the metabolism of breast cancer (metabolic reprogramming) which is now written at line 28 of the revised manuscript.

As recommended, we have also deleted the table-1 from the introduction part which has now been placed in new or 2^nd section titled ‘Status of Metastasis with Breast Cancer Subtypes, Metabolic rewiring, EMT and MET-An Insight.

Comment 2: In the ‘2. The concept of metabolic rewiring, EMT, MET’, and ‘3. The substantial implication of the EMT process in breast cancer progression’ it is recommended to combined the two parts. Avoid talking too many details in this molecular and cellular mechanisms in the cancer development.

Response 2: As suggested, we have combined sections 2 and 3 and included as subheading. Additionally, this section is revised to make it impactful. As suggested, we have also avoided to discuss the molecular and cellular mechanisms in cancer development; also omitted the unnecessary content. However, it is necessary to clear the EMT process mechanism in physiology as well as in cancer. Therefore, it is explained in detail along with figure 1.

Comment 3: ‘4. Current Metabolomic Approaches’, it is recommended that the authors can give a summary of the metabolomics approaches used either in the different breast cancer subtypes or different expressions of EMT markers.

Response 3: We have mentioned the number of metabolomic approaches used either in different breast cancer subtypes or different expressions of EMT markers in the first para of Section 3.

Also, we have combined the section 4 and section 5 into section 3 ‘Metabolomics of Breast Cancer in Driving the EMT Marker Expression Levels’ in the revised manuscript. Additionally, we have explained metabolomics applied to each class of metabolites such as glucose metabolism, lipid metabolism, and amino acid metabolism with its influence on EMT markers in breast cancer.

Comment 4: ‘The implication of metabolomics in driving the EMT profiling of breast cancer hallmarks. This is the most important part of your manuscript. It is recommended to give a summary of the metabolites altered in the different breast cancer subtypes or different expressions of EMT markers.

Response 4: As suggested we have revised the title, abstract and the content of the manuscript in revised manuscript.

We have made some additional content in the revised manuscript in track change mode. Like-

A new table to detail the summary of metabolites altered to mediate EMT markers ad their inhibitors to retard EMT program in breast cancer as table 3.
The table titled “Exogenous blockers of EMT/MET program in breast cancer” is now revised and is renamed as Table 4 titled “Exogenous Blockers of EMT program in breast cancer”.

Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript presented by Dr Ajay Kumar Pal and colleagues is focused on EMT in Breast cancer, in particularly to the role of metabolism in these processes. The review is appealing, but some points should be more investigated:

-The authors should rewrite the abstract.

-line 28.The authors write: "These variables can be classified into two categories..." only two? Is "variables" the correct terms?

Line 81: after the classification, the authors should introduce that TNBC subtypes express the androgen Receptor (AR).

-Are there clinical trials in which are used drugs for blocking the EMT?

- The authors present a beautiful picture resuming EMT, but it is too generic. They should add a picture resuming what happens in Breast (physiological vs pathological (cancer) conditions). Why the cells migrate in normal breast and why in cancerous breast? and why they start with the EMT program?

Author Response

Reviewer 3:

The manuscript presented by Dr. Ajay Kumar Pal and colleagues is focused on EMT in Breast cancer, in particularly to the role of metabolism in these processes. The review is appealing, but some points should be more investigated:

Comment 1: -The authors should rewrite the abstract.

Response 1: As suggested, the abstract of the manuscript has been revised in the revised manuscript.

Comment 2: -line 28. The authors write: "These variables can be classified into two categories..." only two? Is "variables" the correct terms?

Response 2: The variables written at line 28, have been omitted as reviewer 2 suggested to omit the cancer introduction from line 27 to 42. The breast cancer subtypes and molecular classification table have been placed under separate heading as 2^nd section “Status of Metastasis with Breast Cancer Subtypes, Metabolic rewiring, EMT and MET-An Insight”

Comment 3: Line 81: after the classification, the authors should introduce that TNBC subtypes express the androgen Receptor (AR).

Response 3: As suggested, authors have included LAR subtypes of breast cancer in track change mode in the revised manuscript.

Comment 4: -Are there clinical trials in which drugs are used for blocking the EMT?

Response 4: Yes, we have mentioned the EMT blockers which have been under investigation at clinical trials. Also, we have document repurposed metabolic inhibitors of EMT program under table 3 and 4.

Comment 5: - The authors present a beautiful picture resuming EMT, but it is too generic. They should add a picture resuming what happens in Breast (physiological vs pathological (cancer) conditions). Why the cells migrate in normal breast and why in cancerous breast? and why they start with the EMT program?

Response 5: As suggested, Authors have modified the graphical abstract in which migration of normal breast and breast cancer is done; also mentioned why EMT program start. Also, Figure 1 details the “EMT categorization based on epithelial plasticity” in which we have added its legends in the revised manuscript in track change mode.