Date of Award

1-1-2018

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (ii, xiii, 95 pages) : illustrations (some color)

Dissertation/Thesis Chair

JoEllen Welsh

Keywords

Breast, Vitamin D, Hyaluronic acid, Mammary glands, Epithelial cells

Subject Categories

Molecular Biology

Abstract

Each year over 200,000 American women are diagnosed with breast cancer. Nearly 25% of them are told they have triple negative breast cancer (TNBC), the most aggressive and lethal form, with few targeted treatment options beyond the standard regimen of surgery, chemotherapy, and radiotherapy. Over 40% of TNBC cases overexpress hyaluronan synthase 2 (HAS2), a cell membrane enzyme that synthesizes the extracellular matrix (ECM) polysaccharide hyaluronic acid (HA). HA binds to and activates the cell surface receptor CD44, which is highly enriched on the cell surface of cancer stem cells (CSCs) and has been associated with epithelial to mesenchymal transition (EMT), cancer cell invasion and metastasis, and resistance to chemotherapy and radiation. These features result in decreased time to relapse and poor prognosis of TNBC patients whose tumors overexpress HAS2. Recent studies suggest the metabolically active form of vitamin D (1,25D) may interrupt HA synthesis by down-regulating HAS2 (LaPorta and Welsh 2014). Furthermore, studies from other labs suggest 1,25D sensitizes MCF7 and Hs578t breast cancer cells to radiation (Sundaram and Gewirtz 1999; DeMasters et al. 2006; Mineva et al. 2009). Given that numerous epidemiological studies (Toner et al. 2010; Perez-Lopez et al. 2009; Garland et al. 2007) link vitamin D deficiency with increased cancer risk and that studies from our lab (Wang and Welsh 2010) indicate 1,25D may preserve the genome integrity and differentiated morphology of normal mammary epithelial cells exposed to the DNA damaging agent doxorubicin, vitamin D may be an ideal supplement to improve radiotherapy.

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