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

Abstract

Pulmonary arterial hypertension (PAH) and breast cancer disproportionately affect women. <i>BMPR2</i> (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. We combined bioinformatic, epidemiologic, and experimental approaches. Public cancer datasets were mined for <i>BMPR2</i> alterations. In vivo, mammary tumor development and pulmonary hemodynamics were assessed in female <i>Bmpr2</i>^+/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). <i>BMPR2</i> expression was markedly reduced in human breast tumors, with recurrent somatic variants and deep deletions identified. <i>Bmpr2</i>^{<i>+/Δ71</i>} 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 <i>Bmpr2</i>^{<i>+/Δ71</i>} rats showed elevated lung IL-1β and NF-κB activation. In vitro, conditioned media from <i>Bmpr2</i>^{<i>+/Δ71</i>} tumors induced proliferation of <i>Bmpr2</i>^{<i>+/Δ71</i>} 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 <i>BMPR2</i> 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. These findings identify a reciprocal association between breast cancer and PAH mediated by defective <i>BMPR2</i> signaling and tumor-associated inflammation. Breast cancer may act as a "second hit," unmasking <i>BMPR2</i>-related susceptibility to PAH, underscoring BMPR2 as a shared molecular vulnerability with implications for surveillance of at-risk populations.