The role of the tissue microenvironment in resistance and susceptibility of the rat mammary gland to carcinogenesis
N-nitrosomethylurea (NMU) administration to rats of several susceptible strains leads to
rapid, reproducible, tumor production. The Copenhagen (COP) rat strain, however, is
completely resistant to NMU carcinogenesis. The cause of this resistance is yet unknown.
Using tissue recombination experiments, our lab has shown that the mammary gland stroma
is the "gatekeeper" for tu... read moremorigenesis; also, NMU-exposed stroma transformed non-exposed
mammary epithelial cells (MECs) while non-exposed stroma combined with exposed MECs
produced normal ductal structures. Here, I hypothesize that the tumor-resistant
phenotype of COP rats is due to stromal-mediated stabilization of tissue-wide
disruptions in the mammary gland that develop following carcinogenic exposure. In order
to generate a surrogate model for tissue recombinations, I proposed a three-dimensional
(3D) culture model that recapitulates the biochemical and biophysical forces required
for the formation of normal structures found in the mammary gland. I detail the
characterization of an epithelial cell line for use in hormone-responsive 3D culture.
Co-culture of human MECs with rat fibroblasts in floating collagen gels results in the
formation of multicellular structures. NMU treated fibroblasts from susceptible
Wistar-Firth (WF) animals are involved in the formation of highly variable structures
with low biological quality. Expression data derived from COP and WF cleared fat pads
following NMU exposure is analyzed. I propose to study stromal factors involved in COP
resistance and further, to compare stromal-epithelial interactions between resistant COP
rats and Wistar-Furth rats, an NMU-susceptible rat strain. This work will give new
insights into the understanding of COP resistance and broaden our understanding of
stromal contributions to induction or inhibition of carcinogenesis in both of these rat
strains. Those insights, in turn, will better inform us about carcinogenesis in humans.
Theoretical challenges to the current prevailing theory of carcinogenesis are given and
used to explain the thesis findings as well as put into context how altered development
influences tumor susceptibility. The outcomes of the experiments detailed here are
important for furthering our understanding of the process of tumorigenesis, provide a
possible explanation for autonomous tumor remission and, more broadly, aim to widen the
focus of treatment beyond the breast epithelial
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Genetics.
Advisors: Ana Soto, and Carlos Sonnenschein.
Committee: Philip Hinds, Pamela Yelick, and Al Gustafson.
Keyword: Biology.read less