NIPT-based prenatal screening of maternal Xq28 copy number variations in a cohort of 80,371 pregnancies.

Breast cancer remains the most common malignancy among women worldwide () and the leading cause of cancer-related deaths in women, with an estimated 2.3 million new cases and 670,000 deaths globally in 2022 (,). Although notable progress has been made in early diagnosis and comprehensive treatment strategies, tumor migration continues to be the primary cause of treatment failure and patient mortality (,). The invasion and migration of tumor cells constitute a multi-step complex process, involving metabolic reprogramming, epithelial-mesenchymal transition and remodeling of the tumor microenvironment (). Among these, metabolic dysregulation, an emerging hallmark of cancer, serves a key role in providing precursors for macromolecular synthesis and maintaining redox homeostasis. In particular, dysregulated amino acid metabolism has been closely associated with malignant tumor progression (). Branched-chain amino acids (BCAAs), including leucine, isoleucine and valine, serve not only as key substrates for protein synthesis but also as notable signaling molecules and energy sources (). BCAA metabolism is frequently dysregulated in cancer and the key enzyme BCAA transaminase 1 (BCAT1) has been implicated in tumor progression (). BCAT1 catalyzes the initial step of BCAA catabolism, sustaining intracellular BCAA reserves to fuel anabolic processes such as mTOR signaling and nucleotide synthesis (,). In breast cancer, BCAT1 is upregulated in aggressive subtypes including triple-negative breast cancer (TNBC) and this upregulation is associated with poor prognosis (). Specifically, immunohistochemical analysis of breast cancer tissue microarrays in a previous study confirmed that high BCAT1 expression is associated with higher histological grade (Nottingham grading system), lymph node migration and worse prognosis (). Functional studies have demonstrated that BCAT1 promotes breast cancer cell proliferation, migration and invasion, partly by activating mTOR signaling and sustaining intracellular BCAA reserves (,), with emerging evidence implicating downstream pathways such as SHOC2-Ras-ERK in TNBC (). BCAT1 has also been associated with endocrine therapy resistance; specifically, its upregulation sustains the proliferation of antiestrogen-resistant and estrogen receptor (ER)α breast cancer cells (). However, despite these advances, key knowledge gaps remain regarding the oncogenic functions and underlying mechanisms of BCAT1 in TNBC, particularly its contribution to migration through metabolic reprogramming (,,). To the best of our knowledge, the majority of mechanistic studies have focused on ER models, and the specific role of BCAT1 in TNBC migration, particularly its contribution through metabolic reprogramming, has not been fully elucidated. Notably, whether pharmacological targeting of BCAT1-mediated BCAA metabolism can suppress TNBC progression has not been explored, to the best of our knowledge. Due to the potent pro-metastatic functions of BCAT1 in TNBC, identifying agents that modulate BCAT1 activity and BCAA metabolism may offer novel therapeutic opportunities in the future.