Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients’ body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.
Metastasizing cancer cells must adapt their metabolism to the nutrient environment of distant organs. We performed a loss-of-function CRISPR screen against Solute Carrier Transporters (SLCs) in a breast cancer mouse model to define nutrient requirements for lung and liver metastases. Most SLC transporter dependencies of metastases were organ-specific such as the mitochondrial iron importer Slc25a37 (mitoferrin-1, Mfrn1), whose loss inhibited liver but not lung metastasis. Accordingly, SLC25A37 was highly expressed in liver compared to lung metastases of breast cancer patients. Functionally, Slc25a37 expression was induced by HIF1α to support heme synthesis. This enabled cancer cells to grow in hypoxic liver regions because they utilized heme to synthesize the lipophilic antioxidant bilirubin. Treating mice with a ferroptosis inhibitor fully restored the capacity of Slc25a37 deficient cancer cells to grow in the liver. Thus, we defined the nutrient transport liabilities of lung and liver metastases and identified Slc25a37-dependent bilirubin synthesis as a requirement of liver metastasis to resist ferroptosis.
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