Investigation of phosphoserine aminotransferase 1(PSAT1) in breast cancer progression.

phosphoserine;aminotransferase;PSAT;breast;cancer

Stephanie Metcalf

University:University of Louisville

Department:Biochemistry and Molecular Biology

关键词: phosphoserine;    aminotransferase;    PSAT;    breast;    cancer;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=4516&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

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.