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Title: An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival

The concept that a breast cancer patient's menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient's risk for distant metastases.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Oncotarget
Additional Journal Information:
Journal Volume: 5; Journal Issue: 12; Journal ID: ISSN 1949-2553
Publisher:
Impact Journals
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; estrous cycle; mammary glad; RNA-sequencing; Type-1 interferon; low-dose radiation (LDIR); immunity; breast cancer; genetic susceptibility
OSTI Identifier:
1407216

Snijders, Antoine M., Langley, Sasha, Mao, Jian-Hua, Bhatnagar, Sandhya, Bjornstad, Kathleen A., Rosen, Chris J., Lo, Alvin, Huang, Yurong, Blakely, Eleanor A., Karpen, Gary H., Bissell, Mina J., and Wyrobek, Andrew J.. An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival. United States: N. p., Web. doi:10.18632/oncotarget.2148.
Snijders, Antoine M., Langley, Sasha, Mao, Jian-Hua, Bhatnagar, Sandhya, Bjornstad, Kathleen A., Rosen, Chris J., Lo, Alvin, Huang, Yurong, Blakely, Eleanor A., Karpen, Gary H., Bissell, Mina J., & Wyrobek, Andrew J.. An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival. United States. doi:10.18632/oncotarget.2148.
Snijders, Antoine M., Langley, Sasha, Mao, Jian-Hua, Bhatnagar, Sandhya, Bjornstad, Kathleen A., Rosen, Chris J., Lo, Alvin, Huang, Yurong, Blakely, Eleanor A., Karpen, Gary H., Bissell, Mina J., and Wyrobek, Andrew J.. 2014. "An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival". United States. doi:10.18632/oncotarget.2148. https://www.osti.gov/servlets/purl/1407216.
@article{osti_1407216,
title = {An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival},
author = {Snijders, Antoine M. and Langley, Sasha and Mao, Jian-Hua and Bhatnagar, Sandhya and Bjornstad, Kathleen A. and Rosen, Chris J. and Lo, Alvin and Huang, Yurong and Blakely, Eleanor A. and Karpen, Gary H. and Bissell, Mina J. and Wyrobek, Andrew J.},
abstractNote = {The concept that a breast cancer patient's menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient's risk for distant metastases.},
doi = {10.18632/oncotarget.2148},
journal = {Oncotarget},
number = 12,
volume = 5,
place = {United States},
year = {2014},
month = {6}
}