Ovarian status modulates endocrine and neuroinflammatory responses to a murine mammary tumor

Abstract

Breast cancer patients have increased circulating inflammatory markers and mammary tumors increase neuroinflammation in rodent models. Menopausal status is not only important in the context of breast cancer as circulating estrogen influences tumor progression, but also because estrogen is anti-inflammatory and an essential modulator of endocrine function in the brain and body. Here, we manipulated "menopause" status (ovary-intact and ovariectomized) in an ER+ mouse mammary tumor model to determine the extent to which ovarian status modulates: 1) tumor effects on estrogen concentrations and signaling in the brain, 2) tumor effects on estrogen-associated neurobiology and inflammation, and 3) the ability for tumor resection to resolve the effects of a tumor. We hypothesized that reduced circulating estradiol (E2) following ovariectomy exacerbates tumor-induced peripheral and central inflammation. Notably, we observed ovarian-dependent modulation on tumor-induced peripheral outcomes, including E2-dependent processes and, to a lesser degree, circulating inflammatory markers. In the brain, ovariectomy exacerbated neuroinflammatory markers in select brain regions and modulated E2-related neurobiology due to a tumor and/or resection. Overall, our data suggest that ovarian status has moderate implications for tumor-induced alterations in neuroendocrinology and neuroinflammation and mild effects on peripheral inflammatory outcomes in this murine mammary tumor model.

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

“…Protein analyses of plasma determined that the potential confounding effects of CSF1R inhibition on circulating immunity were minimal in BALB/c mice (Figure S2). Indeed, PLX chow did not attenuate the previously reported tumor‐induced elevations in circulating markers 12,36,37 . Thus, the observed neuroinflammatory results were likely driven by the depletion of microglia and not a dampened peripheral‐to‐brain signal.…”

“…Here, we sought to determine the extent to which microglia mediate mammary tumor‐induced neuroinflammation and behavioral side effects in a female mouse cancer model using cellular, molecular, and behavioral analyses. We have previously reported that the gene expression of cytokines and chemokines (e.g., Il1b , Cxcl1 11,12 ) is increased in the brain of this tumor‐bearing model, but the cellular source(s) of these mediators had not yet been determined. Overall, our results indicated that microglia, and likely astrocytes, contribute to mammary tumor‐induced neuroinflammation.…”

“…To investigate the contribution of microglia in tumor‐induced elevations of inflammatory mediators within the brain, region‐specific RT‐qPCR was performed after microglia depletion. We have previously reported that this mammary tumor increases the gene expression of cytokines and chemokines in the hippocampus 11,12,36,37 . Here, we expanded our regions of interest to include the amygdala as it is also implicated in the regulation of fear/affective‐like behaviors 58 and has been minimally studied in relation to cancer‐associated behavioral side effects.…”

“…Indeed, PLX chow did not attenuate the previously reported tumor-induced elevations in circulating markers. 12,36,37 Thus, the observed neuroinflammatory results were likely driven by the depletion of microglia and not a dampened peripheral-to-brain signal.…”

“…7,8 Numerous rodent models of disease and infection demonstrate that peripheral inflammation, like that caused by a solid tumor, can, in turn, elicit neuroinflammation via humoral and neural routes. 9,10 Indeed, we have previously reported that this mammary tumor increases inflammatory mediators in circulation (e.g., CXCL1) 11 and the brain (e.g., Il1b) 12 ; such circulating mediators may directly activate brain cells to secrete their own inflammatory products but the specific molecules involved in this process are not understood. Neuroinflammation is a potential mechanism underlying the etiology of some facets of neuropsychiatric disorders and behavioral deficits.…”