Autocrine prolactin signaling in breast cancer cells leads to metabolic changes and therapeutic opportunities for anti-tumour and anti-bone metastatic treatment

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Biological Sciences

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2026

Author dc:creator

• Lopetegui Gonzalez, Isbel

Advisor dc:contributor.advisor

• Shemanko, Carrie

Committee members dc:contributor.committeemember

• Chua, Gordon
• Cobb, John
• Huang, Carol
• Addison, Christina

• cancer treatment

Statement 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.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/51338

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/124653