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Vitamin D in Normal Breast Tissue Correlates to Early Breast Carcinogenesis

Lan, Shang-Lun
http://orcid.org/0000-0001-8346-043X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1471623716

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Vitamin D, the precursor to the potent steroid hormone calcitriol (1,25(OH)2D), is obtained through synthesis following sunlight exposure, diet and supplements. Vitamin D is first metabolized by CYP2R1 in the liver to produce calcifediol (25(OH)D), a circulating form of vitamin D, which is further converted to 1,25(OH)2D by CYP27B1 primarily in the kidney. 1,25(OH)2D can also be produced by extrarenal CYP27B1 in local tissues, including the breast, functioning in an intracrine, autocrine or paracrine manner. 1,25(OH)2D binds to the vitamin D receptor (VDR) that regulates multiple gene expression. However, most studies reported circulating 25(OH)D level but not the level of 1,25(OH)2D in the target tissue. Laboratory studies indicate that vitamin D should decrease the risk of breast cancer, although epidemiological studies are mixed. Thus, the potential anticancer mechanisms for women remain elusive. In the breast, little is known about the metabolic consequences of vitamin D at the cellular level and how this may potentially impact early breast carcinogenesis. In order to address these issues, blood and tissue samples from 153 healthy women undergoing reduction mammoplasty were used to examine 25(OH)D, 1,25(OH)2D levels and VDR protein expression. These women never had cancer, so findings from their breast tissue would represent biological processes before cancer develops, e.g. early carcinogenesis. I aimed to assess the correlation of blood to breast vitamin D levels, to assess the usefulness of blood levels of 25(OH)D in epidemiology studies as markers for breast levels of 1,25(OH)2D (aim 1), and if there were breast cancer risk factors that affected breast vitamin D levels (aim 2) (Fig. 1.4). I also aimed to determine if there were breast VDR (receptor) that positively correlated to 1,25(OH)2D and 25(OH)D (ligands) (aim 3). To investigate if breast vitamin D alone or with VDR affected breast pre-carcinogenesis, different markers were determined in normal breast tissues for differentiation, proliferation, inflammation, apoptosis and breast involution, and the associations between each of these markers and breast vitamin D. Multiple regression models were built to evaluate the additive effects of breast vitamin D and VDR on each markers (aim 4). Primary human mammalian epithelial cell (HMEC) cultures were used for untargeted metabolomics to examine the metabolomic profiles related to vitamin D in breast cells (aim 5). I established a pilot study method for further cell culture or breast tissue metabolomics and found significantly changed metabolites due to 1,25(OH)2D exposure. My long-term goal is to identify and validate specific pathways and metabolites that can provide new insights into carcinogenic and anti-carcinogenic pathways (e.g., how vitamin D decreases the risk of early breast carcinogenesis).
Peter Shields (Advisor)
Jeffrey Parvin (Committee Member)
Gregory Lesinski (Committee Member)
Michael Freitas (Committee Member)
166 p.
Biomedical Research; Biostatistics; Endocrinology; Epidemiology; Molecular Biology; Oncology; Womens Studies
breast cancer; breast vitamin D; 25OHD; Calcifediol; 1,25OH2D; Calcitriol; reduction mammoplasty; breast risk factor; pre-carcinogenesis; metabolomics; metabolomic profiling; HMEC; cyclic AMP; UHPLC-QTOF-MS

Recommended Citations

Citations

  • Lan, S.-L. (2016). Vitamin D in Normal Breast Tissue Correlates to Early Breast Carcinogenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471623716

    APA Style (7th edition)

  • Lan, Shang-Lun. Vitamin D in Normal Breast Tissue Correlates to Early Breast Carcinogenesis. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1471623716.

    MLA Style (8th edition)

  • Lan, Shang-Lun. "Vitamin D in Normal Breast Tissue Correlates to Early Breast Carcinogenesis." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471623716

    Chicago Manual of Style (17th edition)

osu1471623716
305
© 2016, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.