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Exploring the Role of Aib1 and Foxa1 in Mammary Tumorigenesis Using Transgenic Mouse Models /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Exploring the Role of Aib1 and Foxa1 in Mammary Tumorigenesis Using Transgenic Mouse Models // Sierra Mariette Lusson.
Author:	Lusson, Sierra Mariette,
Description:	1 electronic resource (94 pages)
Notes:	Source: Masters Abstracts International, Volume: 85-01.
Contained By:	Masters Abstracts International85-01.
Subject:	Physiology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30549067
ISBN:	9798379876951

Exploring the Role of Aib1 and Foxa1 in Mammary Tumorigenesis Using Transgenic Mouse Models /
Lusson, Sierra Mariette,

Exploring the Role of Aib1 and Foxa1 in Mammary Tumorigenesis Using Transgenic Mouse Models /Sierra Mariette Lusson. - 1 electronic resource (94 pages)

Source: Masters Abstracts International, Volume: 85-01.

Worldwide, breast cancer is the leading malignancy diagnosed in women accounting for roughly 23% of all cancer cases. Furthermore, breast cancer is the leading cause of cancer related death in women; ER-positive breast cancers being the most lethal of the subtypes. Currently, endocrine treatment is available for breast cancers over expressing the ER, however, patients often develop a resistance to this therapy and relapse after prolonged exposure with high rates of ESR1 mutation occurrences. Mutant ERs have enhanced levels of ER transcriptional activity leading to increased cell proliferation and tumor development. AIB1, a steroid receptor coactivator, interacts with ER in a ligand-dependent fashion to enhance estrogen-dependent transcription and overexpression of AIB1 in AIB1-tg mice was sufficient to drive tumorigenesis. Additionally, transfection studies identified AIB1 as a molecular player in endocrine resistance whereby tamoxifen behaves like an estrogen agonist in ER-positive breast cancer cells that express elevated levels of AIB1, and knockdown of AIB1 restores antitumor effects of tamoxifen. ERdriven transcription is also heavily regulated by pioneer factor FOXA1 whereby knockdown of FOXA1 in MCF-7 tumor cells significantly reduced ER chromatin binding events. Silencing FOXA1 in tamoxifen resistant breast cancer cells significantly reduced ER binding and proliferation suggesting FOXA1 is necessary for hormone independent growth in tamoxifen resistant cancers. In our study, we aim to elucidate the role of ER in luminal breast cancer, specifically exploring members of the ER transcriptome; AIB1 and FOXA1. To understand the role of oncoproteins AIB1 and FOXA1 in early ER positive breast cancer, we have generated two novel inducible mouse models overexpressing AIB1 and FOXA1. AIB1 and FOXA1 genes are expressed under the Tet-Operon and linked to Cre recombinase via IRES then subsequently crossed into the MTB construct to generate AIC/MTB and FIC/MTB mice. Early characterization of the novel models shows positive expression of our transgene within multiple founder strains. Within AIC/MTB mice, RT-qPCR and western blotting analysis show AIB1 mRNA and protein overexpression in our founder lines 1 and 3 following dox induction. AIC virgin mice overexpressing AIB1 had abnormal mammary gland development with significantly greater alveolar budding following 5 8-week dox induction. Overexpression of FOXA1 mRNA and protein have been shown within founder lines 1 and 3 of our FIC/MTB cohorts. FIC mice show abnormal mammary gland development in virgin glands following a 1-week induction, where glands have reduced ductal development. Additionally, FIC models show tumorigenic capacity, whereby FOXA1 overexpression within FIC mammary-derived organoids drove organoid hypertrophy. While much more characterization work remains to be done, my thesis shows a promising start to successful AIB1 and FOXA1 overexpression luminal breast cancer mouse models. The AIC and FIC models will eventually be crossed into the ESR1 Y541S model to investigate the role of AIB1 and FOXA1 in endocrine resistance in the context of a mutated ER. This exploration will hopefully provide a better understanding of escape mechanisms adopted by mutant ER.

English

ISBN: 9798379876951Subjects--Topical Terms:

518431
Physiology.

Exploring the Role of Aib1 and Foxa1 in Mammary Tumorigenesis Using Transgenic Mouse Models /
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520 $a Worldwide, breast cancer is the leading malignancy diagnosed in women accounting for roughly 23% of all cancer cases. Furthermore, breast cancer is the leading cause of cancer related death in women; ER-positive breast cancers being the most lethal of the subtypes. Currently, endocrine treatment is available for breast cancers over expressing the ER, however, patients often develop a resistance to this therapy and relapse after prolonged exposure with high rates of ESR1 mutation occurrences. Mutant ERs have enhanced levels of ER transcriptional activity leading to increased cell proliferation and tumor development. AIB1, a steroid receptor coactivator, interacts with ER in a ligand-dependent fashion to enhance estrogen-dependent transcription and overexpression of AIB1 in AIB1-tg mice was sufficient to drive tumorigenesis. Additionally, transfection studies identified AIB1 as a molecular player in endocrine resistance whereby tamoxifen behaves like an estrogen agonist in ER-positive breast cancer cells that express elevated levels of AIB1, and knockdown of AIB1 restores antitumor effects of tamoxifen. ERdriven transcription is also heavily regulated by pioneer factor FOXA1 whereby knockdown of FOXA1 in MCF-7 tumor cells significantly reduced ER chromatin binding events. Silencing FOXA1 in tamoxifen resistant breast cancer cells significantly reduced ER binding and proliferation suggesting FOXA1 is necessary for hormone independent growth in tamoxifen resistant cancers. In our study, we aim to elucidate the role of ER in luminal breast cancer, specifically exploring members of the ER transcriptome; AIB1 and FOXA1. To understand the role of oncoproteins AIB1 and FOXA1 in early ER positive breast cancer, we have generated two novel inducible mouse models overexpressing AIB1 and FOXA1. AIB1 and FOXA1 genes are expressed under the Tet-Operon and linked to Cre recombinase via IRES then subsequently crossed into the MTB construct to generate AIC/MTB and FIC/MTB mice. Early characterization of the novel models shows positive expression of our transgene within multiple founder strains. Within AIC/MTB mice, RT-qPCR and western blotting analysis show AIB1 mRNA and protein overexpression in our founder lines 1 and 3 following dox induction. AIC virgin mice overexpressing AIB1 had abnormal mammary gland development with significantly greater alveolar budding following 5 8-week dox induction. Overexpression of FOXA1 mRNA and protein have been shown within founder lines 1 and 3 of our FIC/MTB cohorts. FIC mice show abnormal mammary gland development in virgin glands following a 1-week induction, where glands have reduced ductal development. Additionally, FIC models show tumorigenic capacity, whereby FOXA1 overexpression within FIC mammary-derived organoids drove organoid hypertrophy. While much more characterization work remains to be done, my thesis shows a promising start to successful AIB1 and FOXA1 overexpression luminal breast cancer mouse models. The AIC and FIC models will eventually be crossed into the ESR1 Y541S model to investigate the role of AIB1 and FOXA1 in endocrine resistance in the context of a mutated ER. This exploration will hopefully provide a better understanding of escape mechanisms adopted by mutant ER.
520 $a Le cancer du sein est le cancer le plus diagnostique chez les femmes du monde entier, representant environ 23% de tous les cas. De plus, le cancer du sein est la principale cause de mortalite lie au cancer chez les femmes. Les cancers du sein ER (recepteur d'estrogene) -positifs est le plus mortel des sous-types. Actuellement, un traitement endocrinien est disponible pour les cancers du sein sur-exprimant l'ER, cependant, les patientes developpent souvent une resistance a cette therapie et rechutent apres une exposition prolongee avec des taux eleves d'apparition de mutations ESR1. Les ER mutants ont des niveaux accrus d'activite transcriptionnelle, conduisant a une proliferation cellulaire accrue et au developpement de tumeurs. AIB1, un coactivateur des recepteurs steroidiens, interagit avec ER de maniere dependante du ligand pour ameliorer la transcription dependante a l'oestrogene et la surexpression de AIB1 chez les souris AIB1-tg est suffisante pour entrainer l'apparition de tumeurs. De plus, des etudes de transfection ont identifie AIB1 comme un acteur moleculaire de la resistance endocrinienne pour lequel le tamoxifene se comporte comme un agoniste l'oestrogene dans les cellules cancereuses ER-positives qui expriment des niveaux eleves d'AIB1. En plus, l'inactivation d'AIB1 dans ces cellules restaure les effets antitumoraux du tamoxifene. La transcription dirigee par les ER est egalement fortement regulee par le facteur pionnier FOXA1. Inactivation de FOXA1 dans les cellules tumorales MCF-7 a considerablement reduit les evenements de liaison a la chromatine des ER. Enlever l'expression FOXA1 dans les cellules cancereuses du sein resistantes au tamoxifene a considerablement reduit la liaison et la proliferation des ER, ce qui suggere que FOXA1 est necessaire a la croissance independante des hormones dans les cancers resistants au tamoxifene. Dans notre etude, nous visons a elucider le role de ER dans le cancer du sein luminal, en explorant specifiquement les membres du transcriptome de l'ER; AIB1 et FOXA1. Pour comprendre le role des oncoproteines AIB1 et FOXA1 dans le cancer du sein precoce ER positif, nous avons genere deux nouveaux modeles murins inductibles surexprimant AIB1 et FOXA1. Les genes AIB1 et FOXA1 sont exprimes sous l'operon Tet et lies a la recombinase Cre via IRES puis ensuite croises dans la construction MTB pour generer des souris 7 AIC/MTB et FIC/MTB. La caracterisation precoce des nouveaux modeles montre une expression positive de notre transgene au sein de plusieurs souches fondatrices. Chez les souris AIC/MTB, les analyses RTqPCR et IHC montrent une surexpression de l'ARNm et des proteines AIB1 dans nos lignees fondatrices 1 et 3 apres induction de la doxicycline (dox). Les souris vierges AIC surexprimant AIB1 presentent un developpement anormal de leurs glandes mammaires avec un bourgeonnement alveolaire significativement plus important apres une induction a la dox de 8 semaines. La surexpression de l'ARNm et de la proteine FOXA1 a ete demontree dans les lignees fondatrices 1 et 3 de nos cohortes FIC/MTB. Les souris FIC presentent un developpement anormal des glandes mammaires vierges apres une induction d'une semaine, ou les glandes presentent une reduction de leur developpement canalaire. De plus, les modeles FIC montrent une capacite tumorigene, la surexpression de FOXA1 dans les organoides derives du sein FIC entrainant une hypertrophie organoide. Bien qu'il reste encore beaucoup de travail de caracterisation a faire, ma these montre un debut prometteur pour des modeles reussis de cancer du sein luminal de surexpression de AIB1 et FOXA1. Les modeles AIC et FIC seront eventuellement croises avec le modele ESR1 Y541S pour etudier le role de AIB1 et FOXA1 dans la resistance endocrinienne dans le contexte d'un ER mute. Cette exploration fournira une meilleure comprehension des mecanismes d'echappement adoptes par le mutant ER.
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650 4 $a Physiology. $3 518431
650 4 $a Hormones. $3 548778
650 4 $a Womens health. $3 3562508
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650 4 $a Cell cycle. $3 766119
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650 4 $a Gene expression. $3 643979
650 4 $a Medical prognosis. $3 3561728
650 4 $a Steroids. $3 697464
650 4 $a Cyclin-dependent kinases. $3 868634
650 4 $a Deoxyribonucleic acid--DNA. $3 3546879
650 4 $a Biomarkers. $3 2205735
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