Breast Cancer Reveals Latent BMPR2-Related Susceptibility to Pulmonary Hypertension
Background: Pulmonary arterial hypertension (PAH) and breast cancer disproportionately affect women. Bone morphogenetic protein receptor type 2 (BMPR2) mutations, the most common genetic cause of heritable PAH, also exert tumor-suppressive functions, yet their role in linking these diseases remains unclear. Methods: We combined bioinformatic, epidemiologic, and experimental approaches. Public cancer datasets were mined for BMPR2 alterations. In vivo, mammary tumor development and pulmonary hemodynamics were assessed in female Bmpr2?/?71 rats with or without carcinogen (DMBA) exposure. Pulmonary arterial smooth-muscle cells (PASMCs) were exposed to tumor-conditioned media to test inflammatory proliferation. Finally, associations between breast cancer and PAH were examined in the French National Healthcare Database (>9,000 PAH patients). Results: BMPR2 expression was markedly reduced in human breast tumors, with recurrent somatic variants and deep deletions identified. Bmpr2?/?71 rats exhibited spontaneous mammary tumors and, following DMBA exposure, developed exacerbated pulmonary hypertension with increased vascular remodeling and inflammation. Tumor-bearing Bmpr2?/?71 rats showed elevated lung IL-1ß and NF-?B activation. In vitro, conditioned media from Bmpr2?/?71 tumors induced proliferation of Bmpr2?/?71 PASMCs via IL-1ß-dependent signaling, while neutralization of IL-1ß attenuated this effect. Human PASMCs carrying BMPR2 mutations similarly displayed heightened IL-1ß-induced proliferation. Epidemiologically, breast cancer incidence was more than doubled in patients with PAH compared with the general population, and PAH incidence was increased nearly nine-fold among patients with breast cancer, indicating a bidirectional relationship. Conclusions: These findings identify a reciprocal association between breast cancer and PAH mediated by defective BMPR2 signaling and tumor-associated inflammation. Breast cancer may act as a “second hit” unmasking BMPR2-related susceptibility to PAH, underscoring BMPR2 as a shared molecular vulnerability with implications for surveillance of at-risk populations. Overall design: We combined bioinformatic, epidemiologic, and experimental approaches. Public cancer datasets were mined for BMPR2 alterations. In vivo, mammary tumor development and pulmonary hemodynamics were assessed in female Bmpr2?/?71 rats with or without carcinogen (DMBA) exposure. Pulmonary arterial smooth-muscle cells (PASMCs) were exposed to tumor-conditioned media to test inflammatory proliferation. Finally, associations between breast cancer and PAH were examined in the French National Healthcare Database (>9,000 PAH patients).