Date of Award
2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pathology
First Advisor
Brian Cunniff
Abstract
Breast cancer, an abnormal growth of cells in the lobe or duct of the breast, is the most common type of cancer in women and there are about 272 thousand new cases annually. Along with a variety of risk factors, about 10% of all cases are linked to a genetic cause such as a mutation in the BRCA1 or BRCA2 genes. These mutations increase a woman’s risk of breast cancer from a 12.2% chance to an 85.0% chance. A critical factor in breast cancer aggressiveness is the expression of specific hormone receptors including estrogen receptor, progesterone receptor, and human epidermal growth receptor 2. These receptors can greatly impact the tumor’s response to treatment and, therefore, their likely outcome. Due to the specific microenvironment of breast tumors, they most often metastasize to the liver, brain, lungs, and bone partially utilizing the expression of genes related to the epithelial-to-mesenchymal transition pathway. This pathway converts the epithelial cells in the breast tissue into a mesenchymal cell state, making it easier for the cells to circulate in the bloodstream.
Mitochondria are cytoplasmic organelles that are responsible for providing the cell with the energy that it requires to function. To travel around the cell where the energy needs are the greatest, the mitochondria travel along the cell’s microtubules by attaching themselves to motor proteins via a protein complex consisting of Miro1 and TRAK1/2. Tumor cells can take advantage of this system to use this energy for metastasis. Previous work shows that when Miro1 is lost the mitochondria are unable to travel throughout the cell, reducing cell migration and proliferation. Our previous work has shown that deletion of Miro1 from mammary epithelial cells prevents tumor formation in mice.
We hypothesized that pathways including senescence and mitochondrial damage are responsible for the lack of tumor formation in these mice. To investigate these pathways, I conducted immunofluorescence and immunohistochemistry staining of paraffin-embedded and sectioned mouse mammary tissue from control, Miro1 heterozygous, and Miro1 knockout mice with middle T-antigen oncogene activation. In this system, control and Miro1 heterozygous mice form tumors while Miro1 knockout mice do not.
I evaluated the mammary epithelial tissue for senescence markers including p16, p21, p53, and TOMM20. P16 staining was comparable between the wild-type and Miro1 knockout tissue, with the staining located in the fatty tissue and the fibroblasts. There was slightly increased staining of p21 in the wild-type tissue compared to the Miro1 knockout tissue. The intensity of the p53 staining was markedly increased in the strength of staining in the wild-type compared to the Miro1 knockout tissue. TOMM20 staining was significantly decreased in the wild-type and Miro1 heterozygous tissue compared to the Miro1 knockout tissue. Overall, this data indicates that the expression of senescence markers is variably dependent on Miro1 expression, with TOMM20 being the most significantly different between the genotypes. These expression patterns may contribute to a senescence-like phenotype in Miro1 knockout mice and, consequently, a lack of tumor formation.
Language
en
Number of Pages
62 p.
Recommended Citation
Muskat, Alexandra, "The Role Of Miro1 Protein Expression In Breast Cancer" (2025). Graduate College Dissertations and Theses. 2069.
https://scholarworks.uvm.edu/graddis/2069
