Serine synthesis influences tamoxifen response in ER+ human breast carcinoma

Abstract

Estrogen receptor positive breast cancer (ER+ BC) is the most common form of breast carcinoma accounting for approximately 70% of all diagnoses. Although ER-targeted therapies have improved survival outcomes for this BC subtype, a significant proportion of patients will ultimately develop resistance to these clinical interventions, resulting in disease recurrence. Phosphoserine aminotransferase 1 (PSAT1), an enzyme within the serine synthetic pathway (SSP), has been previously implicated in endocrine resistance. Therefore, we determined whether expression of SSP enzymes, PSAT1 or phosphoglycerate dehydrogenase (PHGDH), affects the response of ER+ BC to 4-hydroxytamoxifen (4-OHT) treatment. To investigate a clinical correlation between PSAT1, PHGDH, and endocrine resistance, we examined microarray data from ER+ patients who received tamoxifen as the sole endocrine therapy. We confirmed that higher PSAT1 and PHGDH expression correlates negatively with poorer outcomes in tamoxifen treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis were elevated in tamoxifen-resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of either PSAT1 or PHGDH in each cell type. Overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition on cell proliferation. Conversely, silencing of either PSAT1 or PHGDH resulted in greater sensitivity to 4-OHT treatment in LCC9 tamoxifen-resistant cells. Likewise, the combination of a PHGDH inhibitor with 4-OHT decreased LCC9 cell proliferation. Collectively, these results suggest that overexpression of serine synthetic pathway enzymes contribute to tamoxifen resistance in ER+ BC, which can be targeted as a novel combinatorial treatment option.

Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family

“…The mechanism of Müller cell degeneration in tamoxifen retinal toxicity is not fully understood. In the context of breast cancer cell lines, decreasing serine levels made cells more susceptible to tamoxifen toxicity while increasing serine levels had the opposite effect [ 27 ]. This observation could potentially be explained by elevated serum concentrations of toxic deoxyceramides due to a low-serine environment associated with tamoxifen, though no study has collected data on deoxyceramide levels in patients taking tamoxifen.…”

Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors

“…PSAT1 regulation has been shown to be important in other tumor types, including in pancreatic cancer, in which modulation of PSAT1 expression in LKB1-mutant tumors influences epigenetics and gene expression ( Kottakis et al, 2016 ). Serine metabolism has also been suggested to play a role in the response of ER+ breast cancer cells to endocrine therapy ( Metcalf et al, 2021 ), suggesting a potential role for PSAT1 in drug response. These and other studies highlight the continued importance of serine metabolism in tumors, both as a contributor to cancer biology and a potential therapeutic vulnerability.…”

A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance

“…In cancer cells, serine, a non-essential amino acid, drives growth by providing a one-carbon pool [ 145 ]. De novo synthesis of serine is dependent upon phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase [ 146 ], the levels of which are upregulated in various cancers including breast [ 93 , 147 ]. In conditions of glutamine depletion or mitochondrial dysfunction, cancer cells survive primarily through asparagine metabolism [ 148 ].…”