Exposure to bovine leukemia virus linked to increased risk of breast cancer and cell proliferation

BUEHRING, GC; KRISHNAMURTY S; HUDEN M; BALTZELL K; MARTINEZ CUESTA LUCIA; CERIANI MARIA CAROLINA; ENSEN HM; SWARTZ DA; BLOCK G; LENDEZ PAMELA ANAHI; DOLCINI GUILLERMINA; SHEN H.; JENSEN HM; SISON J; LAWSON J; NIETO FARIAS VICTORIA

Hollywood, California

Congreso; Advances in Breast Cancer Research; 2017

EXPOSURE TO BOVINE LEUKEMIA VIRUSLINKED TO INCREASED RISK OF BREAST CANCER AND CELLPROLIFERATION, Buehring, Gertrude C1; Shen, HuaMin1;Jensen, Hanne M2; Krishnamurty, Savitri3, Swartz, DanielA1; Huden, Mark1; Sison, Jennette4; Block,Gladys1, Baltzell, Kimberly4; Lawson, James5, Lendez, Pamela Anahía,Martínez Cuesta, Lucíaa, Nieto Farias, María Victoriaa,Dolcini, Guillermina Lauraa, Ceriani, Maria Carolinaa,c.Affiliations:1Universityof California, Berkeley; 2University of California, Davis; 3MDAnderson Cancer Center, Houston, TX; 4University of California, SanFrancisco; 5University of New South Wales, Sydney, Australia; FCV-UNCPBA, CIVETAN-CONICET,Tandil, Argentina.      Source of specimens Sample number Frequency of BLV-positive samples Odds ratio (95% confidence interval Probability of chance happening normal Prema-lignant Malig-nant CHTN1, Southern and Eastern Division)2  USA n = 239 30/104 (29%) 8/21 (38%) 67/114 (59%) 3.07 (1.66 ? 5.69) P<.001 Douglass, Hanley, Moir  NSW, Australia3 n=96 19/46 (41%) ----- 40/50 (80%) 4.72 (1.71-13.05) P<.003 MD Anderson Cancer Center, Houston, TX3 n = 216 20/105 (19%) 18/50 (36%) 35/61 (57%) 5.59 (2.76-11.30) P<.0001 UNCPBA, Tandil, Argentina4 n=85 ------ ------ 19/85 (22%) ------ -------- Thepurpose of this study was to compare recent epidemiologic studies to determinefrequency of bovine leukemia virus (BLV) detection in breast tissue indifferent human populations, and association of BLV with a confirmed diagnosisof breast cancer and outcome of commonly used clinical biomarkers.  umerous risk factors are associated withbreast cancer, but what causes the initial molecular and cellular changes fromnormal to malignant is not well understood. Six types of human cancer are caused by viruses, and several viruseshave been studied for their possible role in breast cancer. Bovine leukemiavirus (BLV) is a common virus of US cattle, (38% of beef herds, 89% of dairyherds, 90-100% of large dairy operations). BLV DNA and protein have beenidentified in human tissues. Breast tissue specimens were formalin fixed,paraffin embedded archived tissue sections obtained from the sources listed in thetable.  In situ PCR (IS-PCR) wasperformed on intact deparaffinized sections on glass slides, using primers fromthe tax region (transforming gene), highly conserved and rarely deleted, as are most regions of BLVgenome as tumor progression occurs. taxprimer specificity was confirmed by NCBI (nucleotide BLAST), indicating highesthomology with BLV, and extremely low homology with human genomic sequences,including human endogenous retroviral sequences.Sections were semi-quantitatively scored for density of the IS-PCR productwithin mammary epithelial cells upon microscopic examination by two independentexaminers.  Results are summarized below:1Cooperative Human Tissue Network, PLoSONE 10(9): e0134304, 2015. 2PLoS ONE,PLoS 2017 12(6):e0179367, 20173,4(manuscriptssubmitted);  For31 Australian subjects with breast cancer, an archived normal breast tissue wasavailable from breast surgery performed 3-10 years previously for a conditionunrelated to the subsequent malignancy. For 23(74%) of these, BLV was already present in the normal tissue atleast 3 years before a diagnosis of cancer, consistent with a causativetemporal relationship between BLV infection and subsequent development ofcancer.  In the Argentinian women,conventional prognosis/proliferationbiomarkers (ER, PR, HER2, and Ki67) weretested; BLV presence was associated with moderate to high Ki67 level (p≤0.009) andHER2 overexpression(p≤0.0442),but not with ER and PR, consistent with apossible BLV role in enhanced cell proliferation.BLV?smode of transformation is via the oncogenic protein (Tax) coded for bytax, thegenomic region most highlyconserved and with the least variation. Tax inhibits cellular DNA repair viathe base excision pathway.  DNA damageobserved in breast cancer cells, including driver mutations, couldtheoretically have been initiated due to DNA repair inhibition by BLVinfection.  Elucidatinginitiators for any cancer opens numerous opportunities for primary andsecondary prevention.   For viruses, thereservoir (e.g. BLV-infected cattle) could be reduced, transmission to humanscould be intercepted (e.g. education to avoid raw milk and raw beefappetizers), vaccines could be developed, and elimination of the virus might beachieved by BLV-targeting chemotherapeutic agents.  If BLV initiated specific driver mutationsthese might be targeted as part of personalized secondary prevention and/ortherapy.