Investigating Molecular Mechanisms Driving Breast Cancer Metastasis into the CNS

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.This research project aims to identify unique candidate genes involved in breast cancer metastatic invasion into the central nervous system (CNS). The goal of this study focuses on studying and comparing the genomes of two distinct breast cancer cell lines that model a primary breast cancer and a CNS metastatic variant. These cell lines were established by Yoneda et al. by employing six serial rounds of tumor injection into mice followed by CNS isolation to select a unique clonal cell line that consistently metastasizes to the CNS. Denoted MDA MB-23-BR and MDA MB-231-P by their predilection for CNS metastasis and primary breast tumor growth patterns, respectively, this cell line pair represents a unique functional model for comparing a primary breast cancer and a CNS metastatic clone. Hypothesis: We hypothesized that the BR clone's predilection for CNS metastasis is likely due to unique genetic alterations either at a chromosomal or gene expression level that differ from the primary breast tumor line. The goals of this study aimed to probe the genomes of the MDA MB-23-BR and MDA MB-231-P using array CGH and microarray gene expression profiling to identify these potential 5 differential chromosomal patterns and distinct gene expression profiles between the Br and P cell lines. Results: Initial studies to assess the invasive properties of the BR and P lines showed an approximate five-fold increase in invasion of the BR line compared to the P line by employment of a modified Boyden chamber invasion assay. Results of the array CGH analysis did reveal small regions of relative chromosome loss of the BR line on chromosome 1 and chromosome 10. Results of the gene expression array analysis revealed 138 genes with either 2-fold overexpression or underexpression between the BR and P lines. Canonical Pathway analysis revealed two genes, ADAM19 and GAB1, that may play a role in cell survival and metastasis. Significance: This study successfully identified unique chromosomal and gene expression differences between the MDA MB-231 P and, BR cell lines. These differences, though preliminary, may represent unique genetic regions and genes that facilitate breast cancer metastasis to the CNS and could serve as novel candidates for both biomarker development and chemotherapeutic intervention.This item is part of the College of Medicine - Phoenix Scholarly Projects 2012 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu