title: HIV tropism and decreased risk of breast cancer.
abstract: BACKGROUND
  During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.
  
  
  RESULTS
  We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load≥500 copies/mL. 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 phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002-0.84) 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 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.
authors.affiliation: Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Hessol
authors.forename: Laura A
authors.initials: LA
authors.lastname: Napolitano
authors.forename: Dawn
authors.initials: D
authors.lastname: Smith
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Alexandra
authors.initials: A
authors.lastname: Levine
authors.forename: Mary
authors.initials: M
authors.lastname: Young
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Howard
authors.initials: H
authors.lastname: Minkoff
authors.forename: Kathryn
authors.initials: K
authors.lastname: Anastos
authors.forename: Gypsyamber
authors.initials: G
authors.lastname: D'Souza
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000150:complications / Q000175:diagnosis*; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008137:Longitudinal Studies; D008875:Middle Aged; D011446:Prospective Studies; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012306:Risk; D012307:Risk Factors
chemical_list: D015704:CD4 Antigens; D019713:Receptors, CCR5; D019718:Receptors, CXCR4