Patients receiving chemotherapy for breast cancer have an increased risk of cardiovascular events, particularly postmenopausal women. Although vascular damage, endothelial dysfunction, and oxidative stress have been implicated, the contribution of menopausal status to the vascular mechanisms underlying increased cardiovascular risk remains unclear.
A study published in the Journal of the American College of Cardiology examined whether estrogens confer protection in premenopausal women against neoadjuvant TAC protocol–induced endothelial dysfunction, with particular emphasis on the vascular effects of docetaxel. This is the first study to evaluate the effects of menopausal status on vascular responses to chemotherapy.
The study evaluated oxidative stress, vascular function, and molecular pathways in arterial segments from cancer-free breast tissue of premenopausal and postmenopausal women undergoing surgery with or without prior TAC therapy. Complementary mechanistic studies were conducted in ovariectomized and control female C57BL/6J mice treated with docetaxel or placebo. The investigation focused on vascular tissue responses and molecular pathways rather than clinical cardiovascular outcomes.
TAC-induced endothelial dysfunction was observed in vessels from postmenopausal women, whereas premenopausal women were protected. TAC-induced oxidative stress was also reduced in vessels of premenopausal women, reflected by significantly lower hydrogen peroxide and superoxide levels and lower NOX4 NADPH oxidase expression compared with postmenopausal women.
Non-TAC groups showed no differences between premenopausal and postmenopausal women. TAC resulted in reduced rho-kinase activity and lower inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) at threonine-495 in premenopausal women.
Docetaxel caused molecular changes, hypertension, and endothelial dysfunction only in ovariectomized mice; no such effects were observed in age-matched non-ovariectomized controls.
These findings suggest that TAC-induced vascular dysfunction observed in breast cancer survivors is not present in premenopausal women and are consistent with estrogen-mediated protection against eNOS inhibition and oxidative stress.
