國立虎尾科技大學 |

The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance./
作者:	Charlestin, Verodia.
面頁冊數:	1 online resource (289 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
標題:	Pharmacology. -
電子資源:	click for full text (PQDT)
ISBN:	9798381153095

The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance.
Charlestin, Verodia.

The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance. - 1 online resource (289 pages)

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--University of Notre Dame, 2024.

Includes bibliographical references

The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. We effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer. We focused on the gene hub Aquaporin-7 (human AQP7/mouse Aqp7), a water and glycerol channel, as a novel regulator of breast cancer. We identified AQP7 as a negative prognostic marker of overall survival and metastasis in breast cancer patients. Both in vitro and in vivo experiments showed that AQP7 is required for proliferation, primary tumor progression, and metastasis. Metabolomics on Aqp7 knockdown cells and tumors revealed significantly altered lipid levels, redox, and urea/arginine metabolism. Given the correlation of AQP7 with breast cancer and its involvement in glycerol transport and lipid homeostasis, we investigated AQP7 as a metabolic target for cancer therapy. We find that AQP7 is a critical regulator of metabolic and signaling responses to environmental cellular stresses and of endocrine therapy efficacy in breast cancer metastasis to lung. Our data support AQP7 expression being higher in tumors from breast cancer patients that do not respond to endocrine therapy compared to those that do respond. We investigated whether AQP7 inhibition can increase the therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we see therapeutic synergy between the aquaporin inhibitor Auphen and endocrine therapy tamoxifen, which suggests that Auphen treatment makes the cells more susceptible to tamoxifen. Aqp7 is a novel therapeutic target that provides a metabolic vulnerability in breast cancer and can be targeted to inhibit breast cancer metastasis in combination with endocrine therapy. Together, this study highlights AQP7 as a potential cancer-specific therapeutic vulnerability, and AQP7 inhibition can be exploited for therapeutic benefit in overcoming endocrine therapy resistance.We find that Aqp7 regulates the lower TCA cycle and does not play a key role in the flux of metabolites through glycolysis. Increased expression of hAQP7/mAqp7 significantly alter gene expression, particularly in genes involved in cell proliferation, migration, and response to DNA damage. Structure-function analysis of conserved structural features of Aqp7 plays a role in maintaining metabolic homeostasis. Additionally, these structural features may contribute to additional cancer phenotypes like proliferation and adhesion. Together, this study provides new insight into how AQP7 alters metabolism and AQP7 structure-function relationships, which will provide information that can be used to develop metabolism-targeting therapies and AQP associated drugs for clinical anticancer therapy.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381153095Subjects--Topical Terms:

583819
Pharmacology.
Subjects--Index Terms:

AquaporinIndex Terms--Genre/Form:

554714
Electronic books.

The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance.
LDR:04405ntm a22003857 4500 001 1148727
005 20240930100129.5
006 m o d
007 cr bn ---uuuuu
008 250605s2024 xx obm 000 0 eng d
020 $a 9798381153095
035 $a (MiAaPQ)AAI30689683
035 $a AAI30689683
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Charlestin, Verodia. $3 1474767
245 1 4 $a The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance.
264 0 $c 2024
300 $a 1 online resource (289 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
500 $a Advisor: Littlepage, Laurie E.
502 $a Thesis (Ph.D.)--University of Notre Dame, 2024.
504 $a Includes bibliographical references
520 $a The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. We effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer. We focused on the gene hub Aquaporin-7 (human AQP7/mouse Aqp7), a water and glycerol channel, as a novel regulator of breast cancer. We identified AQP7 as a negative prognostic marker of overall survival and metastasis in breast cancer patients. Both in vitro and in vivo experiments showed that AQP7 is required for proliferation, primary tumor progression, and metastasis. Metabolomics on Aqp7 knockdown cells and tumors revealed significantly altered lipid levels, redox, and urea/arginine metabolism. Given the correlation of AQP7 with breast cancer and its involvement in glycerol transport and lipid homeostasis, we investigated AQP7 as a metabolic target for cancer therapy. We find that AQP7 is a critical regulator of metabolic and signaling responses to environmental cellular stresses and of endocrine therapy efficacy in breast cancer metastasis to lung. Our data support AQP7 expression being higher in tumors from breast cancer patients that do not respond to endocrine therapy compared to those that do respond. We investigated whether AQP7 inhibition can increase the therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we see therapeutic synergy between the aquaporin inhibitor Auphen and endocrine therapy tamoxifen, which suggests that Auphen treatment makes the cells more susceptible to tamoxifen. Aqp7 is a novel therapeutic target that provides a metabolic vulnerability in breast cancer and can be targeted to inhibit breast cancer metastasis in combination with endocrine therapy. Together, this study highlights AQP7 as a potential cancer-specific therapeutic vulnerability, and AQP7 inhibition can be exploited for therapeutic benefit in overcoming endocrine therapy resistance.We find that Aqp7 regulates the lower TCA cycle and does not play a key role in the flux of metabolites through glycolysis. Increased expression of hAQP7/mAqp7 significantly alter gene expression, particularly in genes involved in cell proliferation, migration, and response to DNA damage. Structure-function analysis of conserved structural features of Aqp7 plays a role in maintaining metabolic homeostasis. Additionally, these structural features may contribute to additional cancer phenotypes like proliferation and adhesion. Together, this study provides new insight into how AQP7 alters metabolism and AQP7 structure-function relationships, which will provide information that can be used to develop metabolism-targeting therapies and AQP associated drugs for clinical anticancer therapy.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2024
538 $a Mode of access: World Wide Web
650 4 $a Pharmacology. $3 583819
650 4 $a Oncology. $3 593951
650 4 $a Biochemistry. $3 582831
653 $a Aquaporin
653 $a Breast
653 $a Cancer
653 $a Metabolism
655 7 $a Electronic books. $2 local $3 554714
690 $a 0487
690 $a 0992
690 $a 0419
710 2 $a University of Notre Dame. $b Chemistry and Biochemistry. $3 1465731
710 2 $a ProQuest Information and Learning Co. $3 1178819
773 0 $t Dissertations Abstracts International $g 85-06B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30689683 $z click for full text (PQDT)