Abstract P6-06-02: Low expression levels of hormone receptors (ER-α and PGR) in human breast cancer samples is significantly associated with high-grade human cytomegalovirus-IEA
Authors: A Rahbar, J Touma, H Costa, B Davoudi, K Vetvik, J Geisler, C Söderberg Naucler
Journal: Cancer Research (2017)

Abstract Background: Breast cancer (BC) is the most common type of malignancy and second leading cause of cancer deaths in women worldwide. While contemporary breast cancer therapy allows many patients with localized breast cancer to be cured for their disease, subgroups experience non-curable distant metastasis. In addition, majority of BC cases are considered to be "sporadic", with unknown underlying mechanisms. Thus, it is of major importance to investigate alternative factors that may initiate or promote human breast cancer. Recently, human cytomegalovirus (HCMV) has been detected in samples from primary BC, sentinel lymph nodes and brain metastases obtained from breast cancer patients. However, the oncomodulatory role of HCMV in BC is unknown. Accordingly, the purpose of this study was to elucidate possible correlations between expression of HCMV proteins and established histopathological markers (ER-α, PgR, HER2 etc.) in human breast cancer tissues. Material and Methods: Paraffin embedded breast cancer biopsies (n=62), ductal carcinoma in-situ (DCIS, n=18) and adjacent, benign breast tissue samples (n=42) were retrospectively examined for HCMV-immediate early (IE) and late (LA) proteins by using immunohistochemical techniques. Clinical data were available from the patients´ hospital files provided from the departments of oncology and pathology at Akershus University Hospital, Norway. All patients underwent direct surgery in 2011. The median age at time of surgery was 55 years. All patients received standard adjuvant treatment according to the Norwegian guidelines. Results: HCMV-IE was detected at different levels in all BC cases, DCIS and benign breast tissue samples. Interestingly, high grade HCMV-IE (defined as &amp;gt;50% positive cells in the tumor tissues) was detected in 77% of infiltrating BC and in 39% of DCIS and merely in 7% benign breast tissue samples. High grade HCMV-IE was detected in 40%, 76% and 83% of BC patients with &amp;gt;50-90%, &amp;gt;10-50% and &amp;lt;10% tumor cells expressing PgR in their tumors, respectively (p=0.003). All BC samples with negative or low (0-10%) positive staining for estrogen receptors (ER-α) showed high-grade HCMV-IE staining. In subgroups of patients with increasingly positive staining for ER-α between 10-50% and &amp;gt;50-90% of tumor cells, high HCMV-IE was found in 86% and 74%, respectively (p=0.02). A trend but no significant correlation was found between high-grade HCMV-IE and HER2 negativity (p=0.09). In contrast, High grade HCMV-LA proteins were detected in 5%, 11% and 3% of adjacent benign breast samples, DCIS and infiltrating BC, only. Conclusion: Our findings demonstrate that HCMV- IE but not HCMV-LA proteins are frequently detected in samples obtained from infiltrating BC and DCIS. Although the role of HCMV in carcinogenesis of BC is not defined, our findings suggest a negative correlation between high grade HCMV-IE and hormone receptors in general. All in all, our findings may indicate a possible oncomodulatory role of HCMV-IE in human BC, hampering the expression of hormone receptors and forcing the BC cells to a more aggressive phenotype. The effects of HCMV-induced proteins in human breast cancer cells should be investigated further.Background: Breast cancer (BC) is the most common type of malignancy and second leading cause of cancer deaths in women worldwide. While contemporary breast cancer therapy allows many patients with localized breast cancer to be cured for their disease, subgroups experience non-curable distant metastasis. In addition, majority of BC cases are considered to be "sporadic", with unknown underlying mechanisms. Thus, it is of major importance to investigate alternative factors that may initiate or promote human breast cancer. Recently, human cytomegalovirus (HCMV) has been detected in samples from primary BC, sentinel lymph nodes and brain metastases obtained from breast cancer patients. However, the oncomodulatory role of HCMV in BC is unknown. Accordingly, the purpose of this study was to elucidate possible correlations between expression of HCMV proteins and established histopathological markers (ER-α, PgR, HER2 etc.) in human breast cancer tissues. Material and Methods: Paraffin embedded breast cancer biopsies (n=62), ductal carcinoma in-situ (DCIS, n=18) and adjacent, benign breast tissue samples (n=42) were retrospectively examined for HCMV-immediate early (IE) and late (LA) proteins by using immunohistochemical techniques. Clinical data were available from the patients´ hospital files provided from the departments of oncology and pathology at Akershus University Hospital, Norway. All patients underwent direct surgery in 2011. The median age at time of surgery was 55 years. All patients received standard adjuvant treatment according to the Norwegian guidelines. Results: HCMV-IE was detected at different levels in all BC cases, DCIS and benign breast tissue samples. Interestingly, high grade HCMV-IE (defined as &amp;gt;50% positive cells in the tumor tissues) was detected in 77% of infiltrating BC and in 39% of DCIS and merely in 7% benign breast tissue samples. High grade HCMV-IE was detected in 40%, 76% and 83% of BC patients with &amp;gt;50-90%, &amp;gt;10-50% and &amp;lt;10% tumor cells expressing PgR in their tumors, respectively (p=0.003). All BC samples with negative or low (0-10%) positive staining for estrogen receptors (ER-α) showed high-grade HCMV-IE staining. In subgroups of patients with increasingly positive staining for ER-α between 10-50% and &amp;gt;50-90% of tumor cells, high HCMV-IE was found in 86% and 74%, respectively (p=0.02). A trend but no significant correlation was found between high-grade HCMV-IE and HER2 negativity (p=0.09). In contrast, High grade HCMV-LA proteins were detected in 5%, 11% and 3% of adjacent benign breast samples, DCIS and infiltrating BC, only. Conclusion: Our findings demonstrate that HCMV- IE but not HCMV-LA proteins are frequently detected in samples obtained from infiltrating BC and DCIS. Although the role of HCMV in carcinogenesis of BC is not defined, our findings suggest a negative correlation between high grade HCMV-IE and hormone receptors in general. All in all, our findings may indicate a possible oncomodulatory role of HCMV-IE in human BC, hampering the expression of hormone receptors and forcing the BC cells to a more aggressive phenotype. The effects of HCMV-induced proteins in human breast cancer cells should be investigated further. Citation Format: Rahbar A, Touma J, Costa H, Davoudi B, Vetvik K, Geisler J, Söderberg Naucler C. Low expression levels of hormone receptors (ER-α and PGR) in human breast cancer samples is significantly associated with high-grade human cytomegalovirus-IEA [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-06-02.