Oncotarget

Priority Research Papers:

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

Antoine M. Snijders _, Sasha Langley, Jian-Hua Mao, Sandhya Bhatnagar, Kathleen A. Bjornstad, Chris J. Rosen, Alvin Lo, Yurong Huang, Eleanor A. Blakely, Gary H. Karpen, Mina J. Bissell, Andrew J. Wyrobek

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Oncotarget. 2014; 5:4011-4025. https://doi.org/10.18632/oncotarget.2148

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Abstract

Antoine M. Snijders1, Sasha Langley1, Jian-Hua Mao1, Sandhya Bhatnagar1, Kathleen A. Bjornstad1, Chris J. Rosen1, Alvin Lo1, Yurong Huang1, Eleanor A. Blakely1, Gary H. Karpen1, Mina J. Bissell1 and Andrew J. Wyrobek1

1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA

Correspondence:

Antoine M. Snijders, email:

Keywords: estrous cycle, mammary gland, RNA-sequencing, Type-1 interferon, low-dose ionizing radiation (LDIR), immunity, breast cancer, genetic susceptibility

Received: May 31, 2014 Accepted: June 28, 2014 Published: June 30, 2014

Abstract

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.


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