Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Copyright Statement

All rights reserved. This publication is intended for use solely by faculty, students, and staff of Nova Southeastern University. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, now known or later developed, including but not limited to photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author or the publisher.

Department

College of Pharmacy

First Advisor

Jean J Latimer

Publication Date / Copyright Date

2018

Publisher

Nova Southeastern University

Abstract

Precocious puberty, measured by thelarche or menarche, is a well-established breast cancer risk factor. Using a unique and patented tissue engineering system we established cell lines from 48 primary cultures of normal breast tissue from reduction mammoplasties and used them as an in vitro model of thelarche, quantifying episphere formation and ductal differentiation. Differential ductal formation was observed based on ancestry. In light of African American (AA) precocious thelarche both in vivo and as we observed in vitro, we hypothesized that AA women would exhibit an increased proportion of breast stem cells, with greater potency for differentiation. Five AA cell lines and five European-derived white (EW) cell lines were analyzed. AA cell lines had significantly higher percentages of breast stem cells and these stem cells were more potent than those from EW cell lines, indicating innate differences in stem cells might be responsible for ancestral differences in thelarche. We adapted our tissue engineering system for xenoestrogenic assay development. The formation of epispheres was dose-responsive with estradiol and bisphenol A. Development of a new assay is crucial for banning consumer chemicals that cause cancer related changes in breast development. We then investigated breast cancer cell lines for the role of Nucleotide Excision Repair (NER) in disease progression. Late stage breast cancer cell lines (pre- or post-treatment) manifested significantly higher NER capacity than stage I breast cancer or reduction cell lines. Increased NER capacity may be responsible for chemotherapeutic resistance, consequential of tumor progression. We hypothesized that the driver of higher repair capacity was due to the cancer stem cell populations within these cell lines. Cancer stem cells were flow sorted from breast cancer-derived cell lines and subjected to the functional Unscheduled DNA Synthesis (UDS) assay to assess NER capacity. Cancer stem cells had increased NER capacity compared with non-stem cells from the same cell lines. These data are consistent with breast cancer stem cells driving the increased NER capacity in late stage breast tumors. Developing therapies specific to the breast cancer stem cell compartment, albeit an elusive target, may provide a new treatment modality for resistant, late stage breast tumors.

Disciplines

Pharmacy and Pharmaceutical Sciences

Keywords

Social sciences, Health and environmental sciences, Late stage breast tumors, Menarche, Repair capacity, Thelarche

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