Breast cancer is the second leading cause of cancer death in women in the United States. Metastasis accounts for the death of ~90% of these patients, yet the mechanisms underlying this event remain poorly defined. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that functions to suppress tumorigenesis in mammary epithelial cells (MECs). Interestingly, mammary tumorigenesis converts TGF-beta from a tumor suppressor to a tumor promoter through molecular mechanisms that remain incompletely understood. Changes in tissue compliance promote the acquisition of malignant phenotypes in MECs in part through the activity of the extracellular crosslinking enzyme, lysyl oxidase (LOX), which regulates desmoplastic reactions and metastasis. We show that TGF-beta induces the synthesis and secretion of LOX from normal and malignant MECs, and in breast cancers produced in mice. Additionally, antagonizing LOX activity reduces TGF-beta-mediated invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. We further show that increased extracellular matrix (ECM) rigidity promotes the proliferation of malignant MECs, a cellular reaction that is abrogated by inhibiting TGF-beta signaling or by antagonizing LOX activity.
As a possible mechanism for the influence of matrix rigidity on TGF-beta signaling, we sought to define the microRNA expression profiles induced by TGF-beta and ECM rigidity during metastatic progression. Through global profiling analyses, we identified microRNAs whose expression was induced by TGF-beta and associated with metastatic potential. In doing so, we identified miR-181a as a TGF-beta-regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting their acquisition of EMT, migratory, and invasive phenotypes. Mechanistically, inactivating miR-181a elevated the expression of the pro-apoptotic molecule, Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a activity was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression is dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and is highly predictive for decreased overall survival in human breast cancer patients.
Collectively, our findings implicate LOX and miR-181a expression as novel diagnostic markers for metastatic progression, as well as an innovative therapeutic targets to treat metastatic breast cancers.
","abstract_html":"<p>Breast cancer is the second leading cause of cancer death in women in the United States. Metastasis accounts for the death of ~90% of these patients, yet the mechanisms underlying this event remain poorly defined. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that functions to suppress tumorigenesis in mammary epithelial cells (MECs). Interestingly, mammary tumorigenesis converts TGF-beta from a tumor suppressor to a tumor promoter through molecular mechanisms that remain incompletely understood. Changes in tissue compliance promote the acquisition of malignant phenotypes in MECs in part through the activity of the extracellular crosslinking enzyme, lysyl oxidase (LOX), which regulates desmoplastic reactions and metastasis. We show that TGF-beta induces the synthesis and secretion of LOX from normal and malignant MECs, and in breast cancers produced in mice. Additionally, antagonizing LOX activity reduces TGF-beta-mediated invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. We further show that increased extracellular matrix (ECM) rigidity promotes the proliferation of malignant MECs, a cellular reaction that is abrogated by inhibiting TGF-beta signaling or by antagonizing LOX activity. </p><p>As a possible mechanism for the influence of matrix rigidity on TGF-beta signaling, we sought to define the microRNA expression profiles induced by TGF-beta and ECM rigidity during metastatic progression. Through global profiling analyses, we identified microRNAs whose expression was induced by TGF-beta and associated with metastatic potential. In doing so, we identified miR-181a as a TGF-beta-regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting their acquisition of EMT, migratory, and invasive phenotypes. Mechanistically, inactivating miR-181a elevated the expression of the pro-apoptotic molecule, Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a activity was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression is dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and is highly predictive for decreased overall survival in human breast cancer patients. </p><p>Collectively, our findings implicate LOX and miR-181a expression as novel diagnostic markers for metastatic progression, as well as an innovative therapeutic targets to treat metastatic breast cancers.</p>","abstract_has_math":false,"creators":["Taylor, Molly Ann"],"institution":"Case Western Reserve University School of Graduate Studies","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Pharmacology","degree_department":null,"school":null,"contributors":["Schiemann, William","Noy, Noa"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-03-12","date_published":"2013-03-12","updated_at":"2026-07-24T03:35:52Z","subjects":["Pharmacology","microRNA","TGF-beta","Lysyl Oxidase","breast cancer","Metastasis"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://rave.ohiolink.edu/etdc/view?acc_num=case1354841379","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Schiemann, William","Noy, Noa"]},{"key":"dc:creator","label":"Author","values":["Taylor, Molly Ann"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-03-12"]},{"key":"dc:publisher","label":"Institution","values":["Case Western Reserve University School of Graduate Studies / OhioLINK"]},{"key":"dc:type","label":"Dc Type","values":["Electronic Thesis or Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Case Western Reserve University School of Graduate Studies"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pharmacology","microRNA","TGF-beta","Lysyl Oxidase","breast cancer","Metastasis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://rave.ohiolink.edu/etdc/view?acc_num=case1354841379"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Breast cancer is the second leading cause of cancer death in women in the United States. Metastasis accounts for the death of ~90% of these patients, yet the mechanisms underlying this event remain poorly defined. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that functions to suppress tumorigenesis in mammary epithelial cells (MECs). Interestingly, mammary tumorigenesis converts TGF-beta from a tumor suppressor to a tumor promoter through molecular mechanisms that remain incompletely understood. Changes in tissue compliance promote the acquisition of malignant phenotypes in MECs in part through the activity of the extracellular crosslinking enzyme, lysyl oxidase (LOX), which regulates desmoplastic reactions and metastasis. We show that TGF-beta induces the synthesis and secretion of LOX from normal and malignant MECs, and in breast cancers produced in mice. Additionally, antagonizing LOX activity reduces TGF-beta-mediated invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. We further show that increased extracellular matrix (ECM) rigidity promotes the proliferation of malignant MECs, a cellular reaction that is abrogated by inhibiting TGF-beta signaling or by antagonizing LOX activity.
As a possible mechanism for the influence of matrix rigidity on TGF-beta signaling, we sought to define the microRNA expression profiles induced by TGF-beta and ECM rigidity during metastatic progression. Through global profiling analyses, we identified microRNAs whose expression was induced by TGF-beta and associated with metastatic potential. In doing so, we identified miR-181a as a TGF-beta-regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting their acquisition of EMT, migratory, and invasive phenotypes. Mechanistically, inactivating miR-181a elevated the expression of the pro-apoptotic molecule, Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a activity was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression is dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and is highly predictive for decreased overall survival in human breast cancer patients.
Collectively, our findings implicate LOX and miR-181a expression as novel diagnostic markers for metastatic progression, as well as an innovative therapeutic targets to treat metastatic breast cancers.
"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.201","18.01 MB"]},{"key":"dc:title","label":"Title","values":["The Role of Extracellular Matrix Rigidity and Altered microRNA Expression In TGF-beta-Mediated Breast Cancer Progression"]}]}],"canonical_facts":{"dc:contributor":["Schiemann, William","Noy, Noa"],"dc:creator":["Taylor, Molly Ann"],"dc:date":["2013-03-12"],"dc:description":["Breast cancer is the second leading cause of cancer death in women in the United States. Metastasis accounts for the death of ~90% of these patients, yet the mechanisms underlying this event remain poorly defined. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that functions to suppress tumorigenesis in mammary epithelial cells (MECs). Interestingly, mammary tumorigenesis converts TGF-beta from a tumor suppressor to a tumor promoter through molecular mechanisms that remain incompletely understood. Changes in tissue compliance promote the acquisition of malignant phenotypes in MECs in part through the activity of the extracellular crosslinking enzyme, lysyl oxidase (LOX), which regulates desmoplastic reactions and metastasis. We show that TGF-beta induces the synthesis and secretion of LOX from normal and malignant MECs, and in breast cancers produced in mice. Additionally, antagonizing LOX activity reduces TGF-beta-mediated invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. We further show that increased extracellular matrix (ECM) rigidity promotes the proliferation of malignant MECs, a cellular reaction that is abrogated by inhibiting TGF-beta signaling or by antagonizing LOX activity.
As a possible mechanism for the influence of matrix rigidity on TGF-beta signaling, we sought to define the microRNA expression profiles induced by TGF-beta and ECM rigidity during metastatic progression. Through global profiling analyses, we identified microRNAs whose expression was induced by TGF-beta and associated with metastatic potential. In doing so, we identified miR-181a as a TGF-beta-regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting their acquisition of EMT, migratory, and invasive phenotypes. Mechanistically, inactivating miR-181a elevated the expression of the pro-apoptotic molecule, Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a activity was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression is dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and is highly predictive for decreased overall survival in human breast cancer patients.
Collectively, our findings implicate LOX and miR-181a expression as novel diagnostic markers for metastatic progression, as well as an innovative therapeutic targets to treat metastatic breast cancers.
"],"dc:format":["application/pdf","p.201","18.01 MB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=case1354841379"],"dc:language":["English"],"dc:publisher":["Case Western Reserve University School of Graduate Studies / OhioLINK"],"dc:rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"dc:subject":["Pharmacology","microRNA","TGF-beta","Lysyl Oxidase","breast cancer","Metastasis"],"dc:title":["The Role of Extracellular Matrix Rigidity and Altered microRNA Expression In TGF-beta-Mediated Breast Cancer Progression"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Pharmacology"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Case Western Reserve University School of Graduate Studies"]},"updated_at":"2026-07-24T03:35:52Z"}