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 in this observation. 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.
Highlights
The concept that the menstrual stage of a breast cancer patient at the time of surgery for tumor removal can influence surgical success and survival is of obvious clinical interest, but the evidence remains controversial [16]
We present new evidence in support of the hypothesis that the menstrual stage at the time of tumor surgery may influence personal risk for breast cancer metastases
We identified (1) variations in mammary glands (MG) gene expression as females transitioned through the normal estrous cycle, and (2) variations in peripheral white blood cell (WBC) counts across normal estrous and after exposure to low-dose ionizing radiation (LDIR) in radiation-induced mammary-tumor-susceptible strain of mice, but not detected in the tumor-resistant strain
Summary
The concept that the menstrual stage of a breast cancer patient at the time of surgery for tumor removal can influence surgical success and survival is of obvious clinical interest, but the evidence remains controversial [16]. A number of studies concluded that surgery in the luteal phase of the menstrual cycle (the time between ovulation and menses) was correlated with increased survival [7,8,9,10,11,12]. Further studies showed increased survival in women with high levels of progesterone, which is associated with the luteal phase [13, 14]. Many reports, including several prospective studies, failed to demonstrate a survival difference between surgeries performed at differing menstrual stages [1, 15,16,17]. The absence of a foundational understanding of normal variations in gene expression in the mammary gland across the estrous cycle in controllable model systems makes it difficult to resolve this controversy, and to determine what to measure other than hormonal status and menstrual stage
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