Lindsay D. Strehle

Chemotherapy frequently causes debilitating gastrointestinal symptoms, which are inadequately managed by current treatments. Recent research indicates the gut microbiome plays a role in the pathogenesis of these symptoms. The current study aimed to identify pre-chemotherapy microbiome markers that predict gastrointestinal symptom severity after breast cancer chemotherapy. Fecal samples, blood, and gastrointestinal symptom scores were collected from 59 breast cancer patients before, during, and after chemotherapy. Lower pre-chemotherapy microbiome alpha diversity and abundance of specific microbes (e.g., Faecalibacterium) predicted greater chemotherapy-induced gastrointestinal symptoms. Notably, tumor and diet characteristics were associated with lower pre-chemotherapy alpha diversity. Lower baseline alpha diversity also predicted higher chemotherapy-induced microbiome disruption, which was positively associated with diarrhea symptoms. The results indicate certain cancer patients have lower microbiome diversity before chemotherapy, which is predictive of greater chemotherapy-induced gastrointestinal symptoms and a less resilient microbiome. These patients may be strong candidates for pre-chemotherapy microbiome-directed preventative interventions (e.g., diet change).

Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor‐associated behavioral side effects. The cellular mechanisms by which tumor‐induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor‐induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor‐free controls underwent a sham surgery. Mammary tumors increased IBA1 ⁺ and GFAP ⁺ staining in the amygdala and hippocampus relative to tumor‐free controls. However, tumors did not alter gene expression of Percoll‐enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia‐like behaviors were not altered in tumor‐bearing mice, tumors increased central tendency in the open‐field test; microglia depletion did not reverse this effect. Brain region RT‐qPCR data indicated that microglia depletion attenuated tumor‐induced elevations of neuroinflammatory gene expression in a region‐ and mediator‐specific manner. These results indicate a causal role of microglia in tumor‐induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor‐induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer‐related immune challenges.

Patients with breast cancer 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 estrogen receptor (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) after an 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.