Serine synthesis influences tamoxifen response in ER+ breast cancer
Oestrogen receptor-positive breast cancer (ER+BC) accounts for 70% of all breast cancer cases. Growth of these tumours is driven by oestrogens, and endocrine therapies, such as tamoxifen, inhibit tumour growth by binding ERα and preventing proliferation. Although this is an effective therapeutic approach, endocrine resistance develops in 30% of ER+BC, resulting in disease recurrence.
Phosphoserine aminotransferase 1 (PSAT1), an enzyme within the serine synthetic pathway, has been previously implicated in endocrine resistance. Metcalf and co-workers investigated expression of enzymes in the serine synthetic pathway in ER+BC, in order to determine their potential role in endocrine resistance. The authors used transcriptomic data from patients with ER+BC treated solely with tamoxifen, and found that elevated expression of PSAT1 or phosphoglycerate dehydrogenase (PHGDH) was associated with decreased disease-free survival or relapse-free survival. In vitro studies using breast cancer cell lines representative of endocrine-sensitive (MCF7) or -resistant (LCC9) cancers demonstrated that the expression and activity of PSAT1 and PHGDH were higher in endocrine-resistant cell lines. When expression of PSAT1 was induced in MCF7 cells, tamoxifen-induced growth inhibition was reduced. Reciprocally, loss of PSAT1 or PHGDH in LCC9 cells restored tamoxifen sensitivity, and pharmacological inhibition of PHGDH in LCC9 cells sensitised them to tamoxifen.
These results suggest that overexpression of the serine synthetic pathway contributes to tamoxifen resistance in ER+BC. Selective targeting may help to maintain endocrine sensitivity.
Read the full article in Endocrine-Related Cancer 28 27–37