{"id":{"repo_id":"calgary","oai_identifier":"oai:ucalgary.scholaris.ca:1880/124653"},"canonical_url":"https://search.dev.ndltd.org/etd/calgary/oai:ucalgary.scholaris.ca:1880/124653","repository":{"repo_id":"calgary","name":"University of Calgary","base_url":"https://ucalgary.scholaris.ca/server/oai/request"},"display":{"title":"Autocrine prolactin signaling in breast cancer cells leads to metabolic changes and therapeutic opportunities for anti-tumour and anti-bone metastatic treatment","abstract":"Breast cancer is the most diagnosed cancer among women worldwide and is often associated with osteolytic bone metastasis, characterized by bone destruction. There is growing evidence for a role of autocrine prolactin (PRL) signalling in breast cancer progression, as well as for a role of prolactin in breast cancer-associated bone metastasis. The role of simvastatin in impairing the progression of cancer has also been reported. In this thesis, I characterized cells that were selected for their ability to grow in the bone of immunodeficient mice and subsequently engineered to secrete human PRL (hPRL), as a model of autocrine hPRL-producing bone metastatic breast cancer cells. I found that the cells secrete hPRL into the culture media and respond to hPRL via signal transduction. Bulk RNA sequencing revealed that they express genes that suggest a more aggressive phenotype than MCF7-WT (WT) and empty vector (EV) control cells. It was also observed that they proliferate more than the empty vector control cells and that they induce bone damage when injected directly into the mice’s tibiae. Interestingly, I found that the hPRL-secreting cells had an increased susceptibility to the cholesterol-lowering drug simvastatin (ST) through a mechanism not explained by basal levels of cholesterol, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or acetyl-CoA. In vivo, the drug showed a trend toward slowing the progression of the hPRL-secreting tumours and increasing bone mineral density when used in a therapeutic setting in immunodeficient mice. These findings contribute to the elucidation of novel mechanisms through which autocrine hPRL signalling could stimulate breast cancer progression and bone metastasis and identify potential markers and therapeutic targets that could increase the pipeline of therapies available for the personalized treatment of breast cancer patients.","abstract_html":"Breast cancer is the most diagnosed cancer among women worldwide and is often associated with osteolytic bone metastasis, characterized by bone destruction. There is growing evidence for a role of autocrine prolactin (PRL) signalling in breast cancer progression, as well as for a role of prolactin in breast cancer-associated bone metastasis. The role of simvastatin in impairing the progression of cancer has also been reported. In this thesis, I characterized cells that were selected for their ability to grow in the bone of immunodeficient mice and subsequently engineered to secrete human PRL (hPRL), as a model of autocrine hPRL-producing bone metastatic breast cancer cells. I found that the cells secrete hPRL into the culture media and respond to hPRL via signal transduction. Bulk RNA sequencing revealed that they express genes that suggest a more aggressive phenotype than MCF7-WT (WT) and empty vector (EV) control cells. It was also observed that they proliferate more than the empty vector control cells and that they induce bone damage when injected directly into the mice’s tibiae. Interestingly, I found that the hPRL-secreting cells had an increased susceptibility to the cholesterol-lowering drug simvastatin (ST) through a mechanism not explained by basal levels of cholesterol, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or acetyl-CoA. In vivo, the drug showed a trend toward slowing the progression of the hPRL-secreting tumours and increasing bone mineral density when used in a therapeutic setting in immunodeficient mice. These findings contribute to the elucidation of novel mechanisms through which autocrine hPRL signalling could stimulate breast cancer progression and bone metastasis and identify potential markers and therapeutic targets that could increase the pipeline of therapies available for the personalized treatment of breast cancer patients.","abstract_has_math":false,"creators":["Lopetegui Gonzalez, Isbel"],"institution":"Graduate Studies","degree_name":"Doctor of Philosophy (PhD)","degree_level":null,"degree_discipline":"Biological Sciences","degree_department":null,"school":null,"contributors":[],"advisors":["Shemanko, Carrie"],"committee_chairs":[],"committee_members":["Chua, Gordon","Cobb, John","Huang, Carol","Addison, Christina"],"year":2026,"date_issued":"2026-04-28","date_published":"2026-04-28","updated_at":"2026-07-24T01:30:22Z","subjects":["cancer treatment"],"languages":["en"],"rights":["University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission."],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://dx.doi.org/10.11575/PRISM/51338"],"render_values":[{"text":"https://dx.doi.org/10.11575/PRISM/51338","href":"https://dx.doi.org/10.11575/PRISM/51338","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1880/124653","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Shemanko, Carrie"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Chua, Gordon","Cobb, John","Huang, Carol","Addison, Christina"]},{"key":"dc:creator","label":"Author","values":["Lopetegui Gonzalez, Isbel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2026-06"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-04-29T16:51:23Z"]},{"key":"dc:date.issued","label":"Date","values":["2026-04-28"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Calgary"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biological Sciences"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Calgary"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["cancer treatment"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://dx.doi.org/10.11575/PRISM/51338"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1880/124653"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Breast cancer is the most diagnosed cancer among women worldwide and is often associated with osteolytic bone metastasis, characterized by bone destruction. There is growing evidence for a role of autocrine prolactin (PRL) signalling in breast cancer progression, as well as for a role of prolactin in breast cancer-associated bone metastasis. The role of simvastatin in impairing the progression of cancer has also been reported. In this thesis, I characterized cells that were selected for their ability to grow in the bone of immunodeficient mice and subsequently engineered to secrete human PRL (hPRL), as a model of autocrine hPRL-producing bone metastatic breast cancer cells. I found that the cells secrete hPRL into the culture media and respond to hPRL via signal transduction. Bulk RNA sequencing revealed that they express genes that suggest a more aggressive phenotype than MCF7-WT (WT) and empty vector (EV) control cells. It was also observed that they proliferate more than the empty vector control cells and that they induce bone damage when injected directly into the mice’s tibiae. Interestingly, I found that the hPRL-secreting cells had an increased susceptibility to the cholesterol-lowering drug simvastatin (ST) through a mechanism not explained by basal levels of cholesterol, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or acetyl-CoA. In vivo, the drug showed a trend toward slowing the progression of the hPRL-secreting tumours and increasing bone mineral density when used in a therapeutic setting in immunodeficient mice. These findings contribute to the elucidation of novel mechanisms through which autocrine hPRL signalling could stimulate breast cancer progression and bone metastasis and identify potential markers and therapeutic targets that could increase the pipeline of therapies available for the personalized treatment of breast cancer patients."]},{"key":"dc:title","label":"Title","values":["Autocrine prolactin signaling in breast cancer cells leads to metabolic changes and therapeutic opportunities for anti-tumour and anti-bone metastatic treatment"]}]}],"canonical_facts":{"dc:contributor.advisor":["Shemanko, Carrie"],"dc:contributor.committeemember":["Chua, Gordon","Cobb, John","Huang, Carol","Addison, Christina"],"dc:creator":["Lopetegui Gonzalez, Isbel"],"dc:date":["2026-06"],"dc:date.accessioned":["2026-04-29T16:51:23Z"],"dc:date.issued":["2026-04-28"],"dc:description.abstract":["Breast cancer is the most diagnosed cancer among women worldwide and is often associated with osteolytic bone metastasis, characterized by bone destruction. There is growing evidence for a role of autocrine prolactin (PRL) signalling in breast cancer progression, as well as for a role of prolactin in breast cancer-associated bone metastasis. The role of simvastatin in impairing the progression of cancer has also been reported. In this thesis, I characterized cells that were selected for their ability to grow in the bone of immunodeficient mice and subsequently engineered to secrete human PRL (hPRL), as a model of autocrine hPRL-producing bone metastatic breast cancer cells. I found that the cells secrete hPRL into the culture media and respond to hPRL via signal transduction. Bulk RNA sequencing revealed that they express genes that suggest a more aggressive phenotype than MCF7-WT (WT) and empty vector (EV) control cells. It was also observed that they proliferate more than the empty vector control cells and that they induce bone damage when injected directly into the mice’s tibiae. Interestingly, I found that the hPRL-secreting cells had an increased susceptibility to the cholesterol-lowering drug simvastatin (ST) through a mechanism not explained by basal levels of cholesterol, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or acetyl-CoA. In vivo, the drug showed a trend toward slowing the progression of the hPRL-secreting tumours and increasing bone mineral density when used in a therapeutic setting in immunodeficient mice. These findings contribute to the elucidation of novel mechanisms through which autocrine hPRL signalling could stimulate breast cancer progression and bone metastasis and identify potential markers and therapeutic targets that could increase the pipeline of therapies available for the personalized treatment of breast cancer patients."],"dc:identifier.doi":["https://dx.doi.org/10.11575/PRISM/51338"],"dc:identifier.uri":["https://hdl.handle.net/1880/124653"],"dc:language.iso":["en"],"dc:publisher.institution":["University of Calgary"],"dc:rights":["University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission."],"dc:subject":["cancer treatment"],"dc:title":["Autocrine prolactin signaling in breast cancer cells leads to metabolic changes and therapeutic opportunities for anti-tumour and anti-bone metastatic treatment"],"dc:type":["doctoral thesis"],"thesis:degree_discipline":["Biological Sciences"],"thesis:degree_name":["Doctor of Philosophy (PhD)"],"thesis:institution_name":["University of Calgary"]},"updated_at":"2026-07-24T01:30:22Z"}