Date on Master's Thesis/Doctoral Dissertation
12-2019
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Biochemistry and Molecular Biology
Degree Program
Biochemistry and Molecular Biology, PhD
Committee Chair
Clem, Brian
Committee Member
Klinge, Carolyn
Committee Member
Samuelson, David
Committee Member
Bates, Paula
Committee Member
Ellis, Steve
Author's Keywords
phosphoserine; aminotransferase; PSAT; breast; cancer
Abstract
This dissertation describes my research into the involvement of phosphoserine aminotransferase 1 (PSAT1) in breast cancer progression; specifically, in triple negative breast cancer (TNBC) metastasis and endocrine resistance in estrogen receptor positive breast cancer (ER+BC). Breast cancer is the most common tumor diagnosis among women. While the overall 5-year survival for breast cancer is reaching 90%, the 5-year survival for metastatic disease is only 22%. Metastasis and endocrine resistance combined can affect over 50% of patients. One of the proteins and pathways implicated in both metastasis and endocrine resistance in breast cancer is phosphoserine aminotransferase 1 (PSAT1) and the serine synthetic pathway (SSP). From prior reports and preliminary studies within the lab, I hypothesized that PSAT1 may play a role in metastasis within TNBC and contribute to endocrine within ER+BC. The role of PSAT1 in TNBC metastasis was evaluated via examination of the effects of altered PSAT1 expression on metastatic potential in TNBC cell lines that were “serine synthesis-independent”. Functional relevance of PSAT1 on sensitivity to endocrine therapy was tested in matched endocrine sensitive and endocrine resistant cell lines upon alteration of PSAT1 expression. Through this work, I found that suppression of PSAT1 significantly inhibited the in vitro motility and invasiveness of “serine synthesis-independent” TNBC which was not recapitulated upon suppression of PHGDH, which is the first enzyme within the SSP. I also found that suppression of PSAT1 reduced the number of micro-metastases within the lungs in an experimental metastasis model. In addition, I found that both PSAT1 and PHGDH correlated to poorer progression free survival in multiple patient cohorts, manipulation of PSAT1 or PHGDH in both sensitive and resistant ER+BC cell lines altered sensitivity to 4-hydroxytamoxifen treatment. This body of work has demonstrated that PSAT1 selectively promotes metastasis in “serine synthesis-independent” TNBC via a function unrelated to de novo serine synthesis. It also has shown that both PSAT1 and PHGDH contribute to tamoxifen resistance in ER+BC and thereby implicating a role for the SSP in this context. Taken together, this dissertation demonstrates that PSAT1 contributes to breast cancer progression through promotion of TNBC metastasis and ER+BC endocrine resistance.
Recommended Citation
Metcalf, Stephanie, "Investigation of phosphoserine aminotransferase 1(PSAT1) in breast cancer progression." (2019). Electronic Theses and Dissertations. Paper 3345.
https://doi.org/10.18297/etd/3345
