Breast Cancer Reveals Latent BMPR2-Related Susceptibility to Pulmonary Hypertension

Sep 22, 2026

Uploaded by Oliver

Breast cancer and pulmonary arterial hypertension (PAH) disproportionately affect women, yet the link between them remains unclear. Using bioinformatic mining of public cancer datasets and combined experimental and epidemiologic analyses, investigators assessed BMPR2 alterations and their consequences. In female Bmpr2+/Δ71 rats, carcinogen exposure induced exacerbated pulmonary hypertension with vascular remodeling and inflammation, alongside tumor-driven IL-1β and NF-κB activation. Conditioned tumor media promoted IL-1β–dependent PASMC proliferation, and human data showed bidirectional association between breast cancer and PAH.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Background

Methods

Results

Conclusions

Clinical Perspective

What Is New?

What Are the Clinical Implications?

Circulation ORIGINAL RESEARCH ARTICLE Breast Cancer Reveals Latent BMPR2-Related Susceptibility to Pulmonary Hypertension Victoria Toro, MSc*; Manon Mougin, MSc*; Coline Brossat, MSc; Clement Jambon-Barbara, MSc; Alex Hlavaty, PharmD, MSc; Charles Antoine Guay, MD, PhD; Reem El Kabbout, MSc; Coralie Bilodeau, BSc; Yann Grobs, PhD; Sandra Martineau, MSc; Sandra Breuils-Bonnet, MSc; Antonella Abi-Sleimen, MSc; Gregoire Ruffenach, PhD; Olivier Boucherat, PhD; Malik Bisserier, PhD; Steeve Provencher, MD, MSc; Sebastien Bonnet, PhD; David Montani, MD; Charles Khouri, PhD; François Potus, PhD 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 tumorsuppressive 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+/Δ 71 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+/Δ 71 rats exhibited spontaneous mammary tumors and, following 7,12-dimethylbenz[a]anthracene exposure, developed exacerbated pulmonary hypertension with increased vascular remodeling and inflammation. Tumorbearing Bmpr2+/Δ 71 rats showed elevated lung IL-1β and NF-κB activation. In vitro, conditioned media from Bmpr2+/Δ 71 tumors induced proliferation of Bmpr2+/Δ 71 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. Key Words: animal model ◼ BMPR2 ◼ breast cancer ◼ inflammation ◼ pulmonary hypertension ◼ tumors | Pulmonary arterial hypertension (PAH) is
sive and fatal disease characterized by monary artery vasculopathy leading to | a progresdistal pulincreased | function, and, ultimately, heart failure.1 The disease disproportionately affects women, with a women-to-men ratio of 2:1 and a median survival of fewer than 5 years.2 The pathophysiology of PAH involves pulmonary | | --- | --- | --- | | pulmonary vascular resistance, right ventricular dys- | | | Correspondence to: François Potus, PhD, 2725, chemin Sainte-Foy, Québec, QC G1V 4G5, Canada. Email [francois.potus@criucpq.ulaval.ca](francois.potus@criucpq.ulaval.ca) *V. Toro and M. Mougin contributed equally. Supplemental Material is available with this article at [https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.125.079067](https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.125.079067). For Sources of Funding and Disclosures, see page 531. © 2026 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolter

FAQs

What is the study investigating about BMPR2 and the two diseases?

The study examines how BMPR2 alterations may connect breast cancer and pulmonary arterial hypertension, despite both conditions disproportionately affecting women.

How did the researchers test the role of BMPR2 in animal models?

They assessed mammary tumor development and pulmonary hemodynamics in female Bmpr2+/Δ71 rats, with or without carcinogen exposure, and evaluated pulmonary vascular remodeling and inflammation.

What clinical association did the study find between breast cancer and PAH?

Breast cancer incidence was more than doubled in PAH patients, while PAH incidence increased nearly 9-fold among patients with breast cancer, indicating a bidirectional relationship.

Sep 22, 2026

Uploaded by Oliver