Growth and Proliferation Signaling in Mammary Gland Development and Cancer

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Overview

Title
Growth and Proliferation Signaling in Mammary Gland Development and Cancer
Contributors
LaRocca, Jessica Lyn (creator)
Hixon, Mary (Director)
Filardo, Edward (Reader)
Brody, Julia (Reader)
Freiman, Richard (Reader)
Marsit, Carmen (Reader)
Brown University. BIOMED: Pathobiology (sponsor)
Doi
10.7301/Z0XP736X
Copyright Date
2012
Abstract
Breast cancer is the second most frequently diagnosed cancer and the second leading cause of cancer death in U.S. women. The studies presented in this thesis show that 1) Akt1, a survival gene, is required for normal mammary gland postnatal development and homeostasis. The loss of Akt1 in a C57/Bl6 transgenic mouse model results in a significant delay in postnatal development, followed by permanent changes in adult mammary gland structure. We also demonstrate 2) a critical relationship between Akt1, breast cancer progression, invasion potential, and the epithelial-mesenchymal transition. Significant decreases in the incidence of hyperplastic alveolar nodules (HANs) were found in Akt1-/- female mice following exposure to the environmental carcinogen, dimethylbenza[α]nthracene (DMBA). However, suppression of Akt1 by shRNA in MCF7 human breast carcinoma cells is sufficient to promote the epithelial-mesenchymal transition, and results in a significant increase in the ability to invade in a Matrigel assay. Furthermore, we provide evidence that 3) bisphenol A (BPA), an endocrine disrupting chemical, promotes mouse mammary gland hyperplasia and stimulates the G1/S phase transition of the cell cycle and tamoxifen-resistance in the human breast carcinoma cell line, MCF7. Mice exposed in utero to BPA exhibited multiple alterations in the adult mammary gland, including increased ductal area, terminal end bud number and altered epithelial cell proliferation. In addition, in utero exposure to BPA resulted in an increased in the formation of HANs following a secondary insult to DMBA. Physiologically relevant doses of BPA enhanced MCF7 cell proliferation, stimulation of the G1/S phase transition, and tamoxifen-resistance. Taken together, these studies provide new insights into the influences of Akt1 signaling and environmental exposures on the promotion of mammary gland development and cancer.
Keywords
development
Akt1
Mammary glands
Cancer
Bisphenol A
Notes
Thesis (Ph.D. -- Brown University (2012)
Extent
xv, 218 p.

Citation

LaRocca, Jessica Lyn, "Growth and Proliferation Signaling in Mammary Gland Development and Cancer" (2012). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0XP736X

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