The Biological Role and Translational Implications of the Long Non-Coding RNA GAS5 in Breast Cancer

Round 1

Reviewer 1 Report

In this review, the authors described the biological role and translational implications of the lncRNA GAS5. Overall, the review is well written and well described of how GAS5 could be a potential biomarker and be implemented in the clinic to treat patients in the context of breast cancer. However, I see some important points that are missing in this manuscript (comments below). Therefore, this review still needs further improvement to consider as a publication in Cancers.

 

Comments:

 

·       The correlation between GAS5 and autophagy (ULK1, ULK2) has not been discussed at all. Authors should include the point that how GAS5 expression promote autophagy and eventually kill cancer cells.

·       The regulation of miR-216b by GAS5 and its effect on EMT and invasion in breast cancer has not been pointed out.

·       Including a simplified figure regrading different signaling pathways/mechanisms involved in the downregulation of GAS5 in breast cancer (paragraph 2.2) would be informative and easy to follow an overall understanding of the mechanism for general readers.

·       More mechanistic insights/information should be addressed on how GAS5 levels are modulated by several anticancer drugs (paragraph 3.2).

·       In breast cancer, the downregulation of GAS5 activates miR-222 that is responsible for the chemoresistance to tamoxifen. This point should be discussed.

·       Is GAS5 expression altered in noncancerous other diseases of human? This information could be included in ‘Conclusion’ section as further perspectives.

 

 

Minor:

 

·       In Figure 3, panel A: OncoDB dataset, rearrange (swap the position of each group) the graph of each group, Normal and Primary tumor, to make it coherent with other datasets (UALCAN, Tanric).

 

·       Page 6, line 211: ‘miR-196-5p’ should be corrected as ‘miR-196a-5p’.

 

·       Page 6, line 212: Add references after the sentence “At the time of………and miR-378-5p”.

 

·       Page 4, line 151: Citation should be always by last name of the author. Correct ‘Arshi et al.’ in place of ‘Asghar et al’.

 

·       Page 9, line 357: Replace ‘decade’ with ‘decades’.

 

·       Page 9, line 358: Replace ‘also in’ with ‘including’.

 

 

·       Page 9, line 369: Correct ‘This because’ with ‘It is because’. 

Good. Well written.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Summary

In this review, authors provide a comprehensive overview of the tumor suppressive role of lncRNA GAS5 in breast cancers. Authors first discuss the role of GAS5 in normal human tissue based essentially on its expression levels. Authors primarily focus on and discuss the role and functional mechanism of GAS5 in regulating DNA hypermethylation, acting as a micRNA sponge. Authors discuss studies where dysregulated levels of GAS5 has been shown to promote BC and focus on discussing the multiple known molecular mechanisms of GAS5. In addition, authors also discuss why GAS5 is a good candidate with translational potential of being used as a prognostic marker and potentially a therapeutic target in BC. 

Major Points

1. Authors should include a comment on the histological classification of breast cancer into lobular and ductal cancers based on cell origin in the introduction section.

2. Authors should discuss and provide information regarding the abundance of GAS5 as a tumor suppressor lncRNA in comparison to other known tumor suppressor lncRNAs.

3. Fig 3: Authors should also stratify TCGA BRCA samples by their histological tissue of origin in two groups IDC and ILC and plot the GAS5 expression levels.

Minor Points

1. Line 23: Should be down regulation / suppression and not "down-modulation". Modulation word itself means change in levels but not directionality of the change.

2. Line 24: There should be no "-" in word dysregulation.

3. Line 166. Word "TANRIC" should be capitalized.

In summary, the review article is well written and quite comprehensive however it lacks the histological perspective of breast cancers and how and if the levels of GAS5 are still down regulated irrespective of the histological origin of BC. 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 3 Report

It is a well written and interesting review.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 4 Report

The article provides an overview of the lncRNA GAS5 and its significance in breast cancer. It emphasizes the correlation between decreased GAS5 expression and unfavorable clinical outcomes in breast cancer patients. The potential translational implications of GAS5 as a diagnostic biomarker and for monitoring treatment response are discussed. The therapeutic potential of GAS5 in sensitizing cancer cells, promoting apoptosis, and inhibiting proliferation is also highlighted. The authors suggest that further research is needed to investigate the role of GAS5 in normal breast tissue and breast cancer, and to fully exploit its therapeutic advantages in novel drug development and personalized medicine.

To improve the article, the following questions need to be addressed:

1) Can the authors provide more detailed information about the specific mechanisms by which GAS5 functions in breast cancer? Exploring the molecular pathways and interactions involved would enhance our understanding of GAS5's role.

2) What are the potential side effects or risks associated with manipulating GAS5 expression? Investigating any adverse effects or unintended consequences of targeting GAS5 would present a more comprehensive view of its therapeutic potential.

3) Are there any challenges or limitations associated with using GAS5 as a biomarker or therapeutic target? It is important to discuss any potential hurdles or drawbacks related to utilizing GAS5 in these contexts.

Overall, the existing data on GAS5 in breast cancer lay the groundwork for further exploration of its translational potential. Advancing our understanding of GAS5's role in normal breast tissue and breast cancer will be crucial in harnessing its therapeutic benefits. By leveraging the emerging field of RNA-based biotechnology, further research on GAS5 could lead to improved treatment strategies and personalized approaches for breast cancer patients.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have addressed the raised questions.