Background: Women with HIV/AIDS had a low risk of breast cancer, but with improving antiretroviral therapies their risk gradually increased to that of the general population. Because HIV binding to the CXCR4 chemokine receptor may induce apoptosis of neoplastic breast cells, and because effective antiretroviral therapy retards emergence of CXCR4-using strains of HIV, we hypothesized that HIV tropism for this receptor would reduce breast cancer risk.
Methods: We conducted a breast cancer nested case-control study among women who participated in HIV/AIDS cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 45.7 years) who had stored plasma, with HIV viral load > 500 copies/mL, and collected within 24 months of breast cancer diagnosis. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotyopic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression.
Results: Two (9%) of 22 breast cancer cases had CXCR4-tropic HIV, compared to 19 (29%) of 66 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.02-0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001-0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.
Conclusions: Low breast cancer risk with HIV/AIDS is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.