We examined the relationship between SBP and DBP with the risk of breast cancer in a large population-based cohort study. We found that DBP was associated with an increased risk of breast cancer for postmenopausal women, independently of previous diagnoses of hypertension. We observed a strong positive association of DBP values over 85 mmHg with BC, particularly among postmenopausal women. This finding is in agreement with a study in American population where only DBP but not SBP was associated with BC risk in postmenopausal women 6. Also a recent research using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort reported a positive association of both SBP and DBP categorized by the American Hypertension Association (AHA) and the European Society of Hypertension with BC risk in postmenopausal but not in premenopausal women 5. A study using population from Norway, Austria and Sweden reported an increased BC risk for the highest quintile values of SBP and DBP for all women 7. Conversely, a prospective study from Australia found no association between BP measurements and BC risk 8. However, in a secondary analysis, DBP between baseline and the second follow-up wave were associated with triple negative breast cancer risk. While previous pooled cohort studies have linked hypertension with BC risk 3,4, this study did not find an association of hypertension or SBP with BC risk, presumably due to differences in population characteristics 9,10.
These epidemiological findings must be put in context of the physiopathology of hypertension and breast cancer. The physiological link between high blood pressure and cancer risk is still unclear. One main issue about blood pressure parameters is that while age is positively correlated with SBP increase, DBP is not as straightforward. SBP increases continuously with age, whereas DBP increases until the fifth decade and then slowly decreases from the sixth decade due to vascular stiffness as part of the normal aging process 16. DBP has two major components: peripheral vascular resistance and artery compliance 17,18. Peripheral vascular resistance (PVR) is the total resistance to blood flow across the vascular system determined by the small arterioles. Artery compliance refers to the distensibility of the blood vessels due to blood volume, a term which is related to the elasticity of blood vessels 19. If PVR and artery compliance increase, then DBP would increase. However, if age increases with lower artery compliance or large artery stiffness, DBP would decrease 16. Even though there is evidence showing that both peripheral (muscular) and central (elastic) arteries in hypertensive individuals are stiffer compared to normotensive individuals, in individuals with isolated hypertension, where the SBP is increased with a normal DBP value, the stiffness is increased in large aortic but not peripheral arteries 20,21. Hence, increased DBP values might negatively affect blood flow fluctuations in the peripheral vessels affecting organs like the breast.
Furthermore, besides age, other factors increase BP, including decreased baroreceptor and chemoreceptor sensitivity, increased responsiveness to sympathetic nervous system stimuli, altered sodium metabolism, and altered renin-angiotensin metabolism. Additionally, after menopause, women lose estrogen-vascular protective 22. The decrease in endogenous estrogens, mediated by estrogen receptors (ERs), leads to endothelial vasoconstriction, increasing peripheral vascular resistance 23–26. Therefore, lower estrogen levels in blood might also contribute to lower arterial compliance and increased risk of high blood pressure in postmenopausal women 27–29. Thus, slight alterations in the arterial lumen, either functional or structural, result in significant changes in arterial resistance. Moreover, menopause has shown an accelerated age-related rise in sympathetic nerve activity (SNA), related to impaired central modulation of baroreflex function and direct inhibitory influence of estrogen on SNA30. The increased activity of SNA increases the PVD, increasing the blood pressure. However, whether menopause or estrogen have more effects on DBP than SBP has not been reported to the best of our knowledge. However, it may be that in some postmenopausal women with altered central autonomic regulation coupled with enhanced vascular adrenergic sensitivity may be responsible for elevation in DBP and exaggerated pressor responses to exercise and mental stress 30,31.
In postmenopausal women, adipose tissue increases and stroma tissue diminishes in the breast. Adipose cells in breast tissue produce estradiol locally from circulating precursors 32. Therefore, estradiol levels are higher in breast tissue than in the bloodstream, especially in postmenopausal women 33,34. Genotoxic metabolites from estradiol contribute to BC development 35. Hence, high local estrogen production and altered blood flow in breast tissue may contribute to chronic local inflammation, cell proliferation stimulation, and tumor micro-environment enhancement 36. We propose that increased DBP might not be a causal risk factor for BC, but it might be an important contributor to BC development in postmenopausal women. In this context, postmenopausal women with less-aged vessels in the breast area due to local increased estrogen production accompanied by altered high blood flow in the peripheral vessels are more likely to experience BC (Fig. 2).
Proposed biological mechanisms for explaining hypertension and breast cancer association include chronic inflammation process, modification in apoptosis activation, and disequilibrium in the renin-angiotensin system 37–45, which might be related to BP components, but further research is needed. SBP has been associated with breast cancer in other studies 5. SBP is more related to the cardiac stroke volume than the PVR. However, as PVR increases, SBP will also increase but not as much as DBP 46,47.
Being overweight or obese has been related to breast cancer risk 48 and hypertension 49. We analyzed the association of DBP and breast cancer risk by BMI subgroups and found no interaction, which means that the effect of DBP on breast cancer risk is independent of women BMI.
This study has some limitations. First, there is a lack of information on changes over time for BP measurements and some potential confounding self-reported variables, which may result in misclassification bias. Furthermore, we lack information on the type of hypertension treatment or antihypertensive drug used in hypertensive individuals, evidence suggested association with breast cancer risk50, which may have reduced the strength of hypertension associated with breast cancer. However, the adjusted model including hypertension diagnosis as a confounding variable and the secondary analysis excluding hypertensive individuals showed similar results, meaning that previous hypertension diagnosis did not affect the relationship between DBP and BC incidence.
One of the challenges of working with blood pressure measurements is its classification. The criteria used to define blood pressure cut-offs have been changing over the last few decades depending upon different approaches. We selected the cut-offs of the 2020 International Society Hypertension guidelines as our categorization criteria due to their recent publication, worldwide use, and tailored use in low and high resources settings 14.
Despite the limitations, the strengths of our study include its prospective study design in a large cohort, the availability of objectively measured systolic and diastolic blood pressure by trained staff and the high accuracy of breast cancer diagnoses retrieved for the KCCR. This study is the first in our knowledge to examine the association of BP measurements and breast cancer risk in an Asian large-based population cohort. Moreover, the number of participants and BC cases were similar among premenopausal and postmenopausal women, which allows us to draw conclusions. Additionally, detailed information of established risk factors for breast cancer such as reproductive factors, family history of breast cancer, smoking, hormone replacement treatment use and lifestyle risk factors was available, enabling adjustment for potential confounders.
In summary, this study suggests that higher DBP is associated with an increased BC risk in postmenopausal women. We propose that DBP is associated with an increased probability of breast cancer, but it is not necessarily a causal factor. Thus, managing and lowering DBP will partially influence BC incidence, but DBP value could be used for the risk calculation of BC occurrence. This observation suggests the importance of DBP to estimate BC risk, particularly in postmenopausal women. This association, however, requires further research in larger samples and the utterly potential mechanisms involved needs to be clarified.