Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer

Brianne M. Cruickshank; Marie Claire D. Wasson; Justin M. Brown; Wasundara Fernando; Jaganathan Venkatesh; Olivia L. Walker; Fiorella Morales‐quintanilla; Margaret L. Dahn; Cheryl A. Dean; Dejan Vidovic; Carter Vaniderstine; Graham Dellaire; Paola Marcato

doi:10.3390/cancers13112644

Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer

Brianne M. Cruickshank, Marie Claire D. Wasson, Justin M. Brown, Wasundara Fernando, Jaganathan Venkatesh, Olivia L. Walker, Fiorella Morales‐quintanilla, Margaret L. Dahn, Cheryl A. Dean, Dejan Vidovic, Carter Vaniderstine, Graham Dellaire, Paola Marcato

Medicine

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Triple‐negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non‐coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluor^high CSCs, and is associated with worse outcomes among basal‐like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient‐derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin‐Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR‐190a‐3p, miR‐ 937‐5p, miR‐22‐5p, miR‐30b‐3p, and miR‐6870‐5p. We confirmed the novel interaction between PART1 and miR‐937‐5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line‐specific effects in terms miRNA‐PART1 interactions and gene regu-lation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

Original language	English
Article number	2644
Journal	Cancers
Volume	13
Issue number	11
DOIs	https://doi.org/10.3390/cancers13112644
Publication status	Published - Jun 1 2021

Bibliographical note

Funding Information:
Acknowledgments: P.M. and G.D. are Senior Scientists of the Beatrice Hunter Cancer Research In‐ stitute (BHCRI). B.M.C., M.L.D., and were supported by Nova Scotia Research and Innovation Grad‐ uate Scholarships and Killam Laureate scholarships. M.L.D. was also supported by CGS‐D award from the CIHR. B.M.C. and D.V. were also supported by a Master’s award from the CIHR. M.‐ C.D.W., J.M.B., O.L.W. are partly supported by Genomics in Medicine scholarships from the Dal‐ housie Medical Research Foundation (DMRF), Cancer Research Training Program (CRTP) scholar‐ ships funded through the BHCRI and the Terry Fox Research Institute, and Scotia Scholars Awards funded through Research Nova Scotia. M.‐C.D.W. and O.L.W. are also supported by scholarship from Dalhousie University’s Faculty of Medicine. O.L.W. is also supported by a Nova Scotia Grad‐ uate Scholarship. J.V. is supported in part by a postdoctoral fellowship in breast cancer research administered by the DMRF. C.V. was supported by a Scotia Scholars Award funded through the Nova Scotia Health Research Foundation. The PDX‐AIM Core of Baylor College of Medicine that supplied the PDX used in this study is supported by institutional funding from both the Advanced Technology Cores and the Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI‐ CA125123). It is also supported by a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691). The graphical abstract was cre‐ ated with BioRender.com (accessed on 12 May 2021).

Funding Information:
Funding: This research was funded by the Canadian Institutes of Health Research (CIHR, PJT 162313).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

Oncology
Cancer Research

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13112644

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Cruickshank, B. M., Wasson, M. C. D., Brown, J. M., Fernando, W., Venkatesh, J., Walker, O. L., Morales‐quintanilla, F., Dahn, M. L., Dean, C. A., Vidovic, D., Vaniderstine, C., Dellaire, G., & Marcato, P. (2021). Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer. Cancers, 13(11), Article 2644. https://doi.org/10.3390/cancers13112644

Cruickshank, BM, Wasson, MCD, Brown, JM, Fernando, W, Venkatesh, J, Walker, OL, Morales‐quintanilla, F, Dahn, ML, Dean, CA, Vidovic, D, Vaniderstine, C, Dellaire, G & Marcato, P 2021, 'Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer', Cancers, vol. 13, no. 11, 2644. https://doi.org/10.3390/cancers13112644

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title = "Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer",

abstract = "Triple‐negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non‐coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal‐like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient‐derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin‐Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR‐190a‐3p, miR‐ 937‐5p, miR‐22‐5p, miR‐30b‐3p, and miR‐6870‐5p. We confirmed the novel interaction between PART1 and miR‐937‐5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line‐specific effects in terms miRNA‐PART1 interactions and gene regu-lation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.",

author = "Cruickshank, {Brianne M.} and Wasson, {Marie Claire D.} and Brown, {Justin M.} and Wasundara Fernando and Jaganathan Venkatesh and Walker, {Olivia L.} and Fiorella Morales‐quintanilla and Dahn, {Margaret L.} and Dean, {Cheryl A.} and Dejan Vidovic and Carter Vaniderstine and Graham Dellaire and Paola Marcato",

note = "Funding Information: Acknowledgments: P.M. and G.D. are Senior Scientists of the Beatrice Hunter Cancer Research In‐ stitute (BHCRI). B.M.C., M.L.D., and were supported by Nova Scotia Research and Innovation Grad‐ uate Scholarships and Killam Laureate scholarships. M.L.D. was also supported by CGS‐D award from the CIHR. B.M.C. and D.V. were also supported by a Master{\textquoteright}s award from the CIHR. M.‐ C.D.W., J.M.B., O.L.W. are partly supported by Genomics in Medicine scholarships from the Dal‐ housie Medical Research Foundation (DMRF), Cancer Research Training Program (CRTP) scholar‐ ships funded through the BHCRI and the Terry Fox Research Institute, and Scotia Scholars Awards funded through Research Nova Scotia. M.‐C.D.W. and O.L.W. are also supported by scholarship from Dalhousie University{\textquoteright}s Faculty of Medicine. O.L.W. is also supported by a Nova Scotia Grad‐ uate Scholarship. J.V. is supported in part by a postdoctoral fellowship in breast cancer research administered by the DMRF. C.V. was supported by a Scotia Scholars Award funded through the Nova Scotia Health Research Foundation. The PDX‐AIM Core of Baylor College of Medicine that supplied the PDX used in this study is supported by institutional funding from both the Advanced Technology Cores and the Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI‐ CA125123). It is also supported by a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691). The graphical abstract was cre‐ ated with BioRender.com (accessed on 12 May 2021). Funding Information: Funding: This research was funded by the Canadian Institutes of Health Research (CIHR, PJT 162313). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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T1 - Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer

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AU - Brown, Justin M.

AU - Fernando, Wasundara

AU - Venkatesh, Jaganathan

AU - Walker, Olivia L.

AU - Morales‐quintanilla, Fiorella

AU - Dahn, Margaret L.

AU - Dean, Cheryl A.

AU - Vidovic, Dejan

AU - Vaniderstine, Carter

AU - Dellaire, Graham

AU - Marcato, Paola

N1 - Funding Information: Acknowledgments: P.M. and G.D. are Senior Scientists of the Beatrice Hunter Cancer Research In‐ stitute (BHCRI). B.M.C., M.L.D., and were supported by Nova Scotia Research and Innovation Grad‐ uate Scholarships and Killam Laureate scholarships. M.L.D. was also supported by CGS‐D award from the CIHR. B.M.C. and D.V. were also supported by a Master’s award from the CIHR. M.‐ C.D.W., J.M.B., O.L.W. are partly supported by Genomics in Medicine scholarships from the Dal‐ housie Medical Research Foundation (DMRF), Cancer Research Training Program (CRTP) scholar‐ ships funded through the BHCRI and the Terry Fox Research Institute, and Scotia Scholars Awards funded through Research Nova Scotia. M.‐C.D.W. and O.L.W. are also supported by scholarship from Dalhousie University’s Faculty of Medicine. O.L.W. is also supported by a Nova Scotia Grad‐ uate Scholarship. J.V. is supported in part by a postdoctoral fellowship in breast cancer research administered by the DMRF. C.V. was supported by a Scotia Scholars Award funded through the Nova Scotia Health Research Foundation. The PDX‐AIM Core of Baylor College of Medicine that supplied the PDX used in this study is supported by institutional funding from both the Advanced Technology Cores and the Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI‐ CA125123). It is also supported by a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691). The graphical abstract was cre‐ ated with BioRender.com (accessed on 12 May 2021). Funding Information: Funding: This research was funded by the Canadian Institutes of Health Research (CIHR, PJT 162313). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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N2 - Triple‐negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non‐coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal‐like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient‐derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin‐Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR‐190a‐3p, miR‐ 937‐5p, miR‐22‐5p, miR‐30b‐3p, and miR‐6870‐5p. We confirmed the novel interaction between PART1 and miR‐937‐5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line‐specific effects in terms miRNA‐PART1 interactions and gene regu-lation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

AB - Triple‐negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non‐coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal‐like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient‐derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin‐Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR‐190a‐3p, miR‐ 937‐5p, miR‐22‐5p, miR‐30b‐3p, and miR‐6870‐5p. We confirmed the novel interaction between PART1 and miR‐937‐5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line‐specific effects in terms miRNA‐PART1 interactions and gene regu-lation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

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Lncrna part1 promotes proliferation and migration, is associated with cancer stem cells, and alters the mirna landscape in triple‐negative breast cancer

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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