Evidence for Sympathetic Nervous System Regulation of Breast Cancer Progression

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology, 2012.Breast cancer patients experience chronic emotional stress. A major pathway underlying the stress response is sympathetic nervous system release of norepinephrine (NE) and stimulation of cells expressing α- or β- adrenergic receptors (α-/β-AR). We have detected sympathetic nerve fibers and NE in orthotopic mammary tumors in mice, but their impact on breast tumor pathogenesis is not understood. We hypothesized that stressinduced NE release augments breast tumor growth through AR stimulation. We found that β-AR expression and signaling varied widely in human and mouse breast adenocarcinoma cell lines. 4T1 murine cells expressed no detectable β-AR. In vitro, NE did not alter 4T1 proliferation or protumorigenic cytokine production. In contrast, the human MDA-MB-231 (MB-231) and its brain-metastasizing variant, MB-231BR, expressed very high levels of β-AR. NE or a β2-AR-selective agonist increased production of interleukin-6 (IL-6) by MB-231 and MB-231BR, and elevated vascular endothelial growth factor (VEGF) production by MB-231BR. Therefore, direct tumor effects of NE vary considerably, and are dependent on β-AR expression. In vivo, we tested the impact of social isolation, a stressor that promotes ovarian tumor growth via β-AR activation. In mice socially isolated prior to MB-231 injection, no consistent alterations in tumor growth, VEGF, or IL-6 were observed. Subsequent experiments suggest that timing of stressor exposure relative to tumor initiation determines the impact on tumor pathogenesis. Using the β-AR-negative 4T1 cell line, increased tumor growth was observed in mice treated with desipramine (DMI), a NE reuptake inhibitor that increased NE. Furthermore, in DMI-treated mice, we used an imaging technique called second harmonic generation (SHG) to demonstrate alterations in tumor collagen structure. Tumor growth and metastasis were increased in mice treated with dexmedetomidine (DEX), a highly selective α2- AR agonist, but not isoproterenol (β-AR agonist) or phenylephrine (α1-AR agonist). The DEX-induced alterations in tumor progression were also associated with alterations in collagen structure. These results reveal an undescribed role for α2-AR in tumor progression, and suggest a novel pathway by which elevated NE may promote tumor progression through the extracellular matrix. The results imply that pharmacological AR blockade may be of therapeutic benefit for breast cancer patients

Suicidal Ideation in Pregnant and Postpartum Women Veterans: An Initial Clinical Needs Assessment

IntroductionPregnancy and postpartum, or the perinatal period, are times when women are particularly vulnerable to mental health concerns, including suicidal ideation. Risk factors for suicidal ideation during this period of a woman's life are depression and exposure to trauma, the latter of which may occur during military operations. The number of women veterans in the United States continues to rise, as does their use of maternity benefits. In this pilot study, we examined the feasibility of recruiting pregnant veterans for longitudinal research. We hypothesized that hopelessness and depressive symptoms would be related to suicidal ideation during the perinatal period, and we investigated a possible relationship between post-traumatic stress symptoms (PTSS) and suicidal ideation.Materials and methodsUsing the designated Veterans Affairs (VA) maternity care coordinator's census, we contacted pregnant women veterans for assessment during the 3rd trimester of pregnancy and 6 weeks postpartum at the San Diego VA. Between September 2017 and October 2018, 28 women volunteers completed the following measures: the Columbia-Suicide Severity Rating Scale (C-SSRS); the Beck Hopelessness Scale (BHS); the Edinburgh Postnatal Depression Scale (EPDS); and the PTSD Checklist for DSM-5 (PCL-5). We used correlational analyses and descriptive statistics to determine associations among the measures.ResultsAs gathered from the C-SSRS, over 30% of the veteran women had past lifetime suicide attempts, and over 10% of the veterans had suicidal ideation in the perinatal period. Both depression and PTSS rates neared 30% during pregnancy and postpartum. Hopelessness and depressive symptoms were positively correlated at both time points. While the intensity of lifetime suicidal ideation was correlated with postpartum depressive symptoms, there was no correlation with current suicidal ideation and depressive symptoms. PTSS correlated with both depressive symptoms and hopelessness, but not suicidal ideation, at both time points. There was no correlation between hopelessness and suicidal ideation during the perinatal period in this cohort.ConclusionsIt is important to understand the mental health needs of perinatal veterans given their vulnerability to develop mental health concerns, including suicidal ideation. The unpredicted pattern of correlations determined in this study implies the need for multifaceted measures for safety-related mental health assessment of perinatal veterans, including assessment for PTSS. Strengths of this study include its longitudinal assessment and a sampling from a general population of veterans. Limitations include small sample size, a single gestational time point, and loss of participants who did not return for their postpartum assessment. We demonstrated the feasibility of longitudinal research with pregnant and postpartum veterans, but additional assessment points during the perinatal period could help identify critical times for mental health intervention in this population