School of Public Health
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
Note: Prior to July 1, 2007, the School of Public Health was named the College of Health & Human Performance.
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Item Effects of Tamoxifen Therapy on Breast Carcinogenesis: Epidemiological Associations and Biomechanisms of Action(2022) Ghosh, Rajrupa; Dallal, Cher; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: Tamoxifen, a key chemopreventive and adjuvant endocrine therapy (ET) for breast cancer, is suggested to alter breast cancer risk factors including circulating hormones (estrogen and insulin-like growth factors (IGFs)) and breast density. However, the biological underpinnings of tamoxifen’s effect on these factors remain unclear. This dissertation evaluated effects of tamoxifen on estrogen metabolites (EMs), explored associations between circulating IGFs (IGF-I and IGFBP-3) and volume average sound speed measures (VASS) of breast density, and synthesized evidence from real-world studies to meta-analyze adjuvant ET in relation to contralateral breast cancer (CBC) risk. Methods: Within the Ultrasound Study of Tamoxifen, serial serum samples collected prior to and 12 months after tamoxifen treatment were used to assess longitudinal changes (paired t-tests) in 15 circulating EMs among postmenopausal women (n=23) (Aim 1), and changes in IGFs and VASS (n=53) (Aim 2). Multivariable linear regression examined associations between metabolites of tamoxifen and estrogen among pre- (n=33) and postmenopausal women (n=27) (Aim 1) and concomitant changes in IGFs and VASS (n=53) (Aim 2), 12 months after treatment initiation. In Aim 3, a random effects meta-analysis of observational studies (n=17, 287,576 participants) estimated relative risks (RR) and 95% confidence intervals (CI) for associations between ET and CBC risk among primary breast cancer patients overall, by menopausal status and CBC estrogen receptor (ER)-subtype. Results: Circulating 2-OH and 16-OH pathway EMs, IGF-I, and IGF-I:IGFBP-3 decreased 12 months after tamoxifen initiation (p <0.05; Aims 1 and 2). No associations were observed between concomitant changes in IGFs and VASS among tamoxifen-treated patients (Aim 2). In meta-analyses (Aim 3), endocrine therapy was associated with reduced CBC risk (RR: 0.62, 95% CI: 0.53, 0.73), with a greater reduction observed among premenopausal (RR: 0.58, 95% CI: 0.43, 0.78) versus postmenopausal women (RR: 0.72, 95% CI: 0.60, 0.87). Endocrine therapy reduced the risk of ER-positive (RR: 0.55, 95% CI: 0.43, 0.70) but not ER-negative CBC. Conclusion: The tamoxifen mediated decline of circulating 2-OH, 16-OH and IGF-I provides etiologic insight into the biomechanisms of tamoxifen on breast carcinogenesis. Meta-analyses of observational studies further support a chemopreventive role of endocrine therapy on CBC risk, particularly, ER-positive CBC.Item Breast Cancer Type 1 Susceptibility Protein is a Critical Regulator of Skeletal Muscle Lipid Metabolism(2013) Jackson, Kathryn Campbell; Spangenburg, Espen E; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research consists of three investigations in an effort to determine how circulating estrogens affect skeletal muscle lipid metabolism. Loss of circulating estrogens results in significant increases in visceral fat mass and intramuscular lipids (IMCL). These increases in lipid storage are strongly associated with an elevated risk of developing type 2 diabetes. The first investigation examined how the loss of circulating estrogens alters skeletal muscle metabolic function. Ovariectomy (OVX) resulted in significantly higher visceral fat mass and fatty acid sarcolemmal transporter content, which corresponded with elevated IMCL. Skeletal muscle in the OVX group exhibited lower acyl carnitine species suggesting impaired lipid flux through the mitochondria. Lastly, mitochondrial oxygen consumption rates were impaired in OVX skeletal muscle fibers. The results from this study gave rise to a search to identify an estrogen- sensitive mechanism that regulated lipid transport into the mitochondria. Study two determined for the first time that the BRCA1 protein, which is encoded by an estrogen-sensitive gene, is present and functions as an integral regulator of lipid metabolism in skeletal muscle. Specifically, BRCA1 binds to acetyl CoA carboxylase in response to acute exercise. The in vitro induction of decreases in BRCA1 expression resulted in higher IMCL content, reduced mitochondrial oxygen consumption rates, and elevated reactive oxygen species production. Surprisingly, no differences in BRCA1 content were detected between males and females. In the final study, an inducible, skeletal-muscle specific, BRCA1 KO mouse was developed. Ablation of BRCA1 in skeletal muscle resulted in exercise intolerance and the development of kyphosis. Contrary to our hypothesis, loss of functional BRCA1 in skeletal muscle attenuated the negative metabolic consequences of chronic high fat diet exposure. Collectively, these data provide strong rationale that BRCA1 is an important regulator of skeletal muscle metabolic function and further provide evidence that BRCA1 function is critical in multiple tissues across the body.