Date of Graduation
5-2015
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Wendy Woodward, M.D. Ph.D.
Committee Member
Abenaa Brewster, M.D.
Committee Member
Arvind Rao, Ph.D.
Committee Member
Erik Sulman, M.D., Ph.D.
Committee Member
Naoto T. Ueno, M.D., Ph.D.
Committee Member
Ralf Krahe, Ph.D.
Abstract
With each cycle of pregnancy and lactation, the mammary gland undergoes dramatic changes. Clarkson et al. (2004) and Stein et al. (2004) conducted a detailed analysis of these changes in the mouse mammary gland. Their results showed that tissue remodeling during post-lactational involution period mimics wound healing and tumorigenesis like pathological conditions. This indicates that post-lactational involution may create the microenvironment that initiates the development of precancerous mammary cells and promotes the progression of precancerous cells into cancer cells. Moreover, epidemiological studies have found that triple-negative (TN) breast cancer (BC) is associated with lower frequency and duration of breastfeeding compared to non-TN BC. Inflammatory breast cancer (IBC) accounts for approximately 1 - 5 % of all breast cancers and has significantly lower 5-year survival rates than those for non-IBC. Approximately75% of the IBC samples belongs to the more aggressive subtypes like TN, HER2-enriched, and luminal B breast cancer. Similar to TN BC, TN IBC had been found to have significantly lower frequency and duration of breastfeeding compared to non-TN IBC. The higher frequency of aggressive forms of breast cancer in IBC and the association of TN BC and TN IBC with lower duration of breastfeeding indicate that molecular changes in the mammary gland during post-lactational involution might play roles in development of IBC and TN BC. We hypothesized that gene expression signatures of abrupt post-lactational mammary gland involution correlate with IBC, TN IBC and TN non-IBC. We utilized gene expression data on multiple time-points of the mouse mammary gland development after abrupt weaning to create post-lactational mammary gland involution gene signatures using time-series cluster analysis. Using these gene expression signatures we performed gene set enrichment analysis (GSEA) on human breast cancer gene expression data to identify specific gene expression signatures that are enriched in IBC compared to non-IBC and in TN compared to non-TN in IBC and non-IBC groups. We divided samples in training and validation sets to validate the results of GSEA. We identified 10 statistically significant time-varied gene expression patterns of post-lactational mammary gland involution. We found significant enrichment of one post-lactational involution gene signature in IBC compared to non-IBC. This enriched signature represents genes showing initial up-regulation and later down-regulation during the involution process and significant overlap with genes up-regulated in vascular smooth muscle cells (VSMC) by c-Jun N-terminal protein kinase (JNK1). We identified 3 genes – Involucrin (IVL), Cluster of Differentiation 79B (CD79B), and leptin (LEP) – that were significantly enriched in IBC compared to non-IBC in both training and validation data sets and that are up-regulated in VSMC by JNK1. This data indicate that these genes might be playing roles in IBC development.
Keywords
Post-lactational Involution, Mammary Gland, Breast Cancer, Triple Negative Breast Cancer, Inflammatory Breast Cancer, Gene Signature