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Heritable DNA methylation marks associated with susceptibility to breast cancer

ABSTRACT: Heritable DNA methylation marks associated with susceptibility to breast cancer

PROVIDER: PRJNA414216 | ENA |

REPOSITORIES: ENA

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Project description: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⁺/Δ71 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⁺/Δ71 rats exhibited spontaneous mammary tumors and, following DMBA 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 PASMCs via IL-1β-dependent signaling, while neutralization of IL-1β attenuated this effect. Human PASMCs 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 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.

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Heritable DNA methylation marks associated with susceptibility to breast cancer

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