Breast Cancer Reveals Latent <i>BMPR2</i> -Related Susceptibility to Pulmonary Hypertension

Abstract

BACKGROUND: Pulmonary arterial hypertension (PAH) and breast cancer disproportionately affect women. BMPR2 (bone morphogenetic protein receptor type 2) mutations, the most common genetic cause of heritable PAH, also exert tumor-suppressive functions, but 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 +/Δ71 rats with or without carcinogen (7,12-dimethylbenz[a]anthracene) exposure. Pulmonary arterial smooth muscle cells 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 (9964 patients with PAH). RESULTS: BMPR2 expression was markedly reduced in human breast tumors, with recurrent somatic variants and deep deletions identified. Bmpr2 +/Δ71 rats exhibited spontaneous mammary tumors and, following 7,12-dimethylbenz[a]anthracene exposure, developed exacerbated pulmonary hypertension with increased vascular remodeling and inflammation. Tumor-bearing Bmpr2 +/Δ71 rats showed elevated lung IL-1β and NF-κB activation. In vitro, conditioned media from Bmpr2 +/Δ71 tumors induced proliferation of Bmpr2 +/Δ71 pulmonary arterial smooth muscle cells via IL-1β–dependent signaling, while neutralization of IL-1β attenuated this effect. Human pulmonary arterial smooth muscle cells carrying BMPR2 mutations similarly displayed heightened IL-1β–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 9-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.