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

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.

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

“…Moreover, interferon regulatory factor 7 (IRF7) and its downstream targets (many of which are ISGs shown herein to be repressed by PR), are suppressed in the aforementioned mammary gland tumor metastasis model; restoration of IRF7-signaling suppressed bone metastasis (39). Finally, expression of an interferon-gene signature in a cohort of breast cancer patients was correlated to a lower frequency of breast cancer metastasis (43). Cumulatively, these data suggest mounting evidence that interferon signaling is correlated with tumor development and metastasis.…”

G protein‐coupled estrogen receptor is involved in modulating colonic motor function via nitric oxide release in C57BL/6 female mice

“…The bead propulsion test was carried out before treatment and 30 min after the drug administration. Stages of estrous cycle were assessed by microscopic analysis of vaginal smears in the morning . The animals in proestrous, estrus, and diestrus stage were used for the test ( n = 6 per stage for each group).…”

Type I interferons in anticancer immunity

“…These data support the existence of a mutually reinforcing immunosuppressive circuit that involves tumourinfiltrating pDCs and T Reg cells; however, the molecular mechanisms that underlie such a circuit have yet to be elucidated. Irrespective of this, it seems that a type I IFNrelated genetic signature identified by RNA sequencing predicts metastasisfree survival in patients with breast cancer 32 . This corrobo rates the idea that intratumoural type I IFN signalling stimulates anticancer immunosurveillance and hence may improve disease outcome in patients with cancer.…”