04 February 2019 by Valerie Nadeau

BMPR2 Mutant Rat Model Unexpectedly Develops Spontaneous Breast Tumor But No Pulmonary Hypertension

Background:

BMPR2 mutation is reported in 80% of familial PAH and 20% of idiopathic cases. Recently, a new rat model of hereditary pulmonary arterial hypertension (HPAH) harboring a monoallelic bone morphogenetic protein type II receptor (BMPR2) loss-of-function mutation called Δ71 have been generated. BMPR2 rat model of heritable PAH recapitulates some features of PAH including pulmonary vascular remodeling and slight increased in RVSP with an incomplete penetrance.

Objective:

We used these BMPR2 rats in Quebec City to further study the potential of this model for PAH research.

Methods and Results:

By using these Bmpr2 mutant rat we observed that 27% (95%CI: 7-47) of Bmpr2+/Δ71 rats presenting RVSP greater than 40 mmHg (42 to 58 mmHg) at 8-18 months of age. All rats had normal right ventricular function, as assessed by right heart catheterization and echocardiography measurements. Unexpectedly, we observed that 20% (95%CI:12-28) of the 82 Bmpr2+/Δ71 rats versus 4% (95%CI:0-9) of the 84 age-matched wild-type littermates spontaneously developed mammary masses and ulcerations requiring euthanasia. Mammary masses were histologically diagnosed by an anatomical veterinary pathologist as fibroadenomas (hormone-dependent benign breast tumors predisposing to cancer) and adenocarcinoma in 83% and 17% of cases, respectively. Tumors predominantly occurred in females (93% of cases), were generally observed after postnatal day 322 and were associated with more elevated RVSP (37±11 versus 26±11 mmHg, p=0.05). Mechanistically, we are presently investigating the relationship of BMPR2 signaling and DNA damage response especially BRCA1 in these breast tumors, as well as the impact of BMPR2 mutation on hormonal regulation, both of which may explain the unexpected tumor development.

Conclusions:

BMPR2 rat mutant develop spontanous breast tumors. We are presently charactarizing these tumors and investigating the implication of BMPR2 signaling on both DNA damage repair an hormonal regulation, which are two important features of breast cancer development.

 

About the author


profile picture of Valerie Nadeau

Valerie Nadeau

PhD

CRIUCPQ

Canada

Key Contributors

Valérie Nadeau, Eve Tremblay, Benoit Ranchoux, Marie-Claude Lampron, Roxane Paulin, Olivier Boucherat, Steeve Provencher and Sébastien Bonnet 1 1. Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University, Quebec, Canada


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