BOVINE LEUKEMIA VIRUS IN BREST TISSUE LINKED TO INCREASED CELL PROLIFERATION AND BREAST CANCER RISK

DOLCINI GUILLERMINA LAURA; LENDEZ PAMELA ANAHI; BALTZELL KIMBERLEY; CERIANI CAROLINA; MARTINEZ CUESTA LUCIA; SISON JENNETTE; BUEHRING GC; NIETO FARIAS VICTORIA; KRISHNAMURTY SAVITRI; SHEN HUA MIN

Hollywood, California

Congreso; American association of cancer research -Advances in breast cancer research; 2017

American Association of Cancer Research

Purpose: to compare recent data sets on frequency of bovine leukemia virus (BLV) detection in breast tissue in different human populations, and association of BLV with a confirmed diagnosis of breast cancer, and expression of common clinical biomarkers. Many risk factors are associated with breast cancer, but what causes initial molecular/cellular changes from normal to malignant is not well understood. Six types of human cancer are caused by viruses, and several viruses have been studied for a role in breast cancer. BLV is a common virus of US cattle, (38% of beef herds, 89% of dairy herds, 90-100% of large dairy operations). BLV DNA and protein were previously identified in human tissues. Methods: Breast tissue specimens were archived formalin fixed, paraffin embedded tissue sections from sources in table below. In situ PCR (IS-PCR) was performed on intact deparaffinized sections on glass slides, using primers from the tax region (transforming gene), highly conserved and rarely deleted, as are most BLV genome regions as tumor progression occurs. BLAST sequence comparisons indicated primers had high homology only with BLV, and extremely low homology with human genomic sequences, including human endogenous retroviral sequences. Previous laboratory experiments confirmed this specificity. Sections were semi-quantitatively scored for density of the digoxygenin-labeled IS-PCR product within mammary epithelial cells, upon microscopic examination by two independent examiners. Results: Previous data sets using samples from the Cooperative Human Tissue Network, USA (n=239) and New South Wales, Australia (n=96) showed BLV presence significantly more frequently in malignant tissue than in normal breast tissue from women with no breast cancer history. Odds ratios (OR) and confidence intervals (CI) were 3.07(1.66-5.69), p≥.001 and 4.72(1.71-13.05) p≥.003, respectively. New unpublished data indicates specimens from MD Anderson Cancer Center Houston,TX (n=216) show OR (CI) of 5.59 (2.76-11.30) p≥.0001. Argentinian specimens showed lower frequency 22% in malignant than US (58%) and Australian specimens (80%). Cells proliferation markers, KI67 and HER2 overexpression were significantly associated with BLV presence in Argentinian malignant breast tissues. For 31 Australian subjects with breast cancer, archived normal breast tissues were available from surgery 3-10 years previous for an unrelated condition. For 23(74%) of these, BLV was already present in normal tissue at least 3 years before cancer diagnosis, consistent with a causative temporal relationship between BLV presence and subsequent cancer development. Conclusions: New data indicates Argentinian women have a lower BLV frequency in breast cancer tissue than women in the USA and Australia. Tests for conventional prognosis/proliferation biomarkers (ER, PR, HER2, Ki67) showed BLV presence significantly associated with moderate-high Ki67 level (p≤0.009) and HER2 overexpression (p≤0.0442), consistent with possible BLV role in enhanced cell proliferation. BLV?s mode of transformation is via the oncogenic protein (Tax), which inhibits host cell DNA repair via the base excision pathway. DNA damage observed in breast cancer cells, including driver mutations, could theoretically have been initiated due to DNA repair inhibition by BLV infection. Elucidating initiators for any cancer opens opportunities for primary and secondary prevention. For viruses, the reservoir (e.g. BLV-infected cattle) could be reduced, transmission to humans could be intercepted (e.g. education to avoid raw milk, raw beef appetizers), vaccines could be developed, and elimination of the virus might be achieved by developing BLV-targeting agents. Driver mutations already initiated by BLV might be targeted as part of personalized secondary prevention and/or therapy.