Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of brea...
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Autor*in:	David A. Skaar [verfasserIn] Eric C. Dietze [verfasserIn] Jackelyn A. Alva-Ornelas [verfasserIn] David Ann [verfasserIn] Dustin E. Schones [verfasserIn] Terry Hyslop [verfasserIn] Christopher Sistrunk [verfasserIn] Carola Zalles [verfasserIn] Adrian Ambrose [verfasserIn] Kendall Kennedy [verfasserIn] Ombeni Idassi [verfasserIn] Gustavo Miranda Carboni [verfasserIn] Michael N. Gould [verfasserIn] Randy L. Jirtle [verfasserIn] Victoria L. Seewaldt [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	triple negative breast cancer epigenetics imprinting

Übergeordnetes Werk:	In: Cancers - MDPI AG, 2010, 13(2021), 23, p 6031
Übergeordnetes Werk:	volume:13 ; year:2021 ; number:23, p 6031

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cancers13236031

Katalog-ID:	DOAJ051403811

Internformat


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520			\|a Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
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allfields	10.3390/cancers13236031 doi (DE-627)DOAJ051403811 (DE-599)DOAJ9e2898cfe24c47d2a1bbe86b8234d8d3 DE-627 ger DE-627 rakwb eng RC254-282 David A. Skaar verfasserin aut Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens Eric C. Dietze verfasserin aut Jackelyn A. Alva-Ornelas verfasserin aut David Ann verfasserin aut Dustin E. Schones verfasserin aut Terry Hyslop verfasserin aut Christopher Sistrunk verfasserin aut Carola Zalles verfasserin aut Adrian Ambrose verfasserin aut Kendall Kennedy verfasserin aut Ombeni Idassi verfasserin aut Gustavo Miranda Carboni verfasserin aut Michael N. Gould verfasserin aut Randy L. Jirtle verfasserin aut Victoria L. Seewaldt verfasserin aut In Cancers MDPI AG, 2010 13(2021), 23, p 6031 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:13 year:2021 number:23, p 6031 https://doi.org/10.3390/cancers13236031 kostenfrei https://doaj.org/article/9e2898cfe24c47d2a1bbe86b8234d8d3 kostenfrei https://www.mdpi.com/2072-6694/13/23/6031 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2021 23, p 6031
spelling	10.3390/cancers13236031 doi (DE-627)DOAJ051403811 (DE-599)DOAJ9e2898cfe24c47d2a1bbe86b8234d8d3 DE-627 ger DE-627 rakwb eng RC254-282 David A. Skaar verfasserin aut Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens Eric C. Dietze verfasserin aut Jackelyn A. Alva-Ornelas verfasserin aut David Ann verfasserin aut Dustin E. Schones verfasserin aut Terry Hyslop verfasserin aut Christopher Sistrunk verfasserin aut Carola Zalles verfasserin aut Adrian Ambrose verfasserin aut Kendall Kennedy verfasserin aut Ombeni Idassi verfasserin aut Gustavo Miranda Carboni verfasserin aut Michael N. Gould verfasserin aut Randy L. Jirtle verfasserin aut Victoria L. Seewaldt verfasserin aut In Cancers MDPI AG, 2010 13(2021), 23, p 6031 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:13 year:2021 number:23, p 6031 https://doi.org/10.3390/cancers13236031 kostenfrei https://doaj.org/article/9e2898cfe24c47d2a1bbe86b8234d8d3 kostenfrei https://www.mdpi.com/2072-6694/13/23/6031 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2021 23, p 6031
allfields_unstemmed	10.3390/cancers13236031 doi (DE-627)DOAJ051403811 (DE-599)DOAJ9e2898cfe24c47d2a1bbe86b8234d8d3 DE-627 ger DE-627 rakwb eng RC254-282 David A. Skaar verfasserin aut Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens Eric C. Dietze verfasserin aut Jackelyn A. Alva-Ornelas verfasserin aut David Ann verfasserin aut Dustin E. Schones verfasserin aut Terry Hyslop verfasserin aut Christopher Sistrunk verfasserin aut Carola Zalles verfasserin aut Adrian Ambrose verfasserin aut Kendall Kennedy verfasserin aut Ombeni Idassi verfasserin aut Gustavo Miranda Carboni verfasserin aut Michael N. Gould verfasserin aut Randy L. Jirtle verfasserin aut Victoria L. Seewaldt verfasserin aut In Cancers MDPI AG, 2010 13(2021), 23, p 6031 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:13 year:2021 number:23, p 6031 https://doi.org/10.3390/cancers13236031 kostenfrei https://doaj.org/article/9e2898cfe24c47d2a1bbe86b8234d8d3 kostenfrei https://www.mdpi.com/2072-6694/13/23/6031 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2021 23, p 6031
allfieldsGer	10.3390/cancers13236031 doi (DE-627)DOAJ051403811 (DE-599)DOAJ9e2898cfe24c47d2a1bbe86b8234d8d3 DE-627 ger DE-627 rakwb eng RC254-282 David A. Skaar verfasserin aut Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens Eric C. Dietze verfasserin aut Jackelyn A. Alva-Ornelas verfasserin aut David Ann verfasserin aut Dustin E. Schones verfasserin aut Terry Hyslop verfasserin aut Christopher Sistrunk verfasserin aut Carola Zalles verfasserin aut Adrian Ambrose verfasserin aut Kendall Kennedy verfasserin aut Ombeni Idassi verfasserin aut Gustavo Miranda Carboni verfasserin aut Michael N. Gould verfasserin aut Randy L. Jirtle verfasserin aut Victoria L. Seewaldt verfasserin aut In Cancers MDPI AG, 2010 13(2021), 23, p 6031 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:13 year:2021 number:23, p 6031 https://doi.org/10.3390/cancers13236031 kostenfrei https://doaj.org/article/9e2898cfe24c47d2a1bbe86b8234d8d3 kostenfrei https://www.mdpi.com/2072-6694/13/23/6031 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2021 23, p 6031
allfieldsSound	10.3390/cancers13236031 doi (DE-627)DOAJ051403811 (DE-599)DOAJ9e2898cfe24c47d2a1bbe86b8234d8d3 DE-627 ger DE-627 rakwb eng RC254-282 David A. Skaar verfasserin aut Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens Eric C. Dietze verfasserin aut Jackelyn A. Alva-Ornelas verfasserin aut David Ann verfasserin aut Dustin E. Schones verfasserin aut Terry Hyslop verfasserin aut Christopher Sistrunk verfasserin aut Carola Zalles verfasserin aut Adrian Ambrose verfasserin aut Kendall Kennedy verfasserin aut Ombeni Idassi verfasserin aut Gustavo Miranda Carboni verfasserin aut Michael N. Gould verfasserin aut Randy L. Jirtle verfasserin aut Victoria L. Seewaldt verfasserin aut In Cancers MDPI AG, 2010 13(2021), 23, p 6031 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:13 year:2021 number:23, p 6031 https://doi.org/10.3390/cancers13236031 kostenfrei https://doaj.org/article/9e2898cfe24c47d2a1bbe86b8234d8d3 kostenfrei https://www.mdpi.com/2072-6694/13/23/6031 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2021 23, p 6031
language	English
source	In Cancers 13(2021), 23, p 6031 volume:13 year:2021 number:23, p 6031
sourceStr	In Cancers 13(2021), 23, p 6031 volume:13 year:2021 number:23, p 6031
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	triple negative breast cancer <i<KCNK9</i< epigenetics imprinting Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Cancers
authorswithroles_txt_mv	David A. Skaar @@aut@@ Eric C. Dietze @@aut@@ Jackelyn A. Alva-Ornelas @@aut@@ David Ann @@aut@@ Dustin E. Schones @@aut@@ Terry Hyslop @@aut@@ Christopher Sistrunk @@aut@@ Carola Zalles @@aut@@ Adrian Ambrose @@aut@@ Kendall Kennedy @@aut@@ Ombeni Idassi @@aut@@ Gustavo Miranda Carboni @@aut@@ Michael N. Gould @@aut@@ Randy L. Jirtle @@aut@@ Victoria L. Seewaldt @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	614095670
id	DOAJ051403811
language_de	englisch
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callnumber-first	R - Medicine
author	David A. Skaar
spellingShingle	David A. Skaar misc RC254-282 misc triple negative breast cancer misc <i<KCNK9</i< misc epigenetics misc imprinting misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer
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topic_title	RC254-282 Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer triple negative breast cancer <i<KCNK9</i< epigenetics imprinting
topic	misc RC254-282 misc triple negative breast cancer misc <i<KCNK9</i< misc epigenetics misc imprinting misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc triple negative breast cancer misc <i<KCNK9</i< misc epigenetics misc imprinting misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc triple negative breast cancer misc <i<KCNK9</i< misc epigenetics misc imprinting misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer
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title_full	Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer
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author_browse	David A. Skaar Eric C. Dietze Jackelyn A. Alva-Ornelas David Ann Dustin E. Schones Terry Hyslop Christopher Sistrunk Carola Zalles Adrian Ambrose Kendall Kennedy Ombeni Idassi Gustavo Miranda Carboni Michael N. Gould Randy L. Jirtle Victoria L. Seewaldt
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author-letter	David A. Skaar
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title_sort	epigenetic dysregulation of <i<kcnk9</i< imprinting and triple-negative breast cancer
callnumber	RC254-282
title_auth	Epigenetic Dysregulation of <i<KCNK9</i< Imprinting and Triple-Negative Breast Cancer
abstract	Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
abstractGer	Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
abstract_unstemmed	Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. <i<KCNK9</i< encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, <i<KCNK9</i< gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that <i<KCNK9</i< is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of <i<KCNK9</i<, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (<i<p</i< = 0.006), but not in Caucasians (<i<p</i< = 0.70). <i<KCNK9</i< hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the <i<KCNK9</i< gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the <i<KCNK9</i< DMR predicts for increased TASK3 expression and mitochondrial membrane potential (<i<p</i< < 0.001). This is the first identification of the <i<KCNK9</i< DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the <i<KCNK9</i< DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the <i<KNCK9</i< DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
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