TSH elevation associated with pregnancy problems

Preconception TSH and pregnancy outcomesTSH (thyroid stimulating hormone) when elevated even within the ‘normal’ range at preconception, can result in adverse pregnancy outcomes. Further evidence for this was presented in a studyrecently published in Clinical Endocrinology, that examines whether subclinical hypothyroidism (SCH) has negative effects on pregnancy.

“Subclinical hypothyroidism (SCH), defined as elevated TSH and normal free T4 (fT4) levels, with an incidence of 2–13·7%, is the most common thyroid disorder during pregnancy. SCH has also been associated with adverse foeto-maternal outcomes…”

Thyroid hormone levels before pregnancy

Adverse effects of SCH during the first trimester and after have been documented in earlier studies, but there has been much less data for preconception thyroid hormone levels.

“To the best of our knowledge, this study was the first large-scale study to investigate the association between maternal TSH levels within the 6 months before conception and the risk of adverse pregnancy outcomes in a population at low risk. The second aim was to determine whether the first-trimester specific reference range or nonpregnant reference range for TSH should be applied during preconception evaluation.”

This was a large study, with 248,501 pairs of volunteer couples recruited from a free National Pre-pregnancy Checkups Project from 2010 to 2012 in China, out of which 184,611 women who later became pregnant were examined by measuring maternal thyroid stimulating hormone within 6 months before conception.

“Participants were grouped according to TSH: 0·48–2·49 mIU/l (n = 133 232, 72%), 2·50–4·28 mIU/l (n = 44 239, 24%) and 4·29–10·0 mIU/l (n = 7140, 4%). Multivariable logistic regression models were used to study the association between TSH and pregnancy outcomes.”

Preconception TSH elevation increases risk of adverse pregnancy outcomes

Even when within what is often still considered the normal non-pregnant range, thyroid stimulating hormone elevation predicted pregnancy problems.

“The overall incidence of adverse pregnancy outcomes was 28·6%. Compared with TSH 0·48–2·50 mIU/l, TSH 2·50–4·29 mIU/l was associated with spontaneous abortion [aOR: 1·10,], preterm birth (aOR: 1·09) and operative vaginal delivery (aOR: 1·15, 95% CI: 1·09–1·21), while TSH 4·29–10 mIU/l was correlated with spontaneous abortion (aOR: 1·15), stillbirth (aOR: 1·58), preterm birth (aOR: 1·20), caesarean section (aOR: 1·15) and large for gestational age (LGA) infants (aOR: 1·12).”

The authors discuss the implication of these odds ratios that are small yet significant.

“The present study involving 194 154 subjects demonstrated that preconception high TSH was associated with a small but significant increased risk of overall adverse pregnancy outcomes, including spontaneous abortion, preterm birth and LGA infants, regardless of whether we used first-trimester-specific upper limit (2·50 mIU/l) or nonpregnant reference upper limit (4·29 mIU/l). Our data support that women planning a pregnancy within 6 months should be regarded as ‘pregnant status’ and that closer observation may be required once TSH levels exceed 2·50 mIU/l, rather than the nonpregnant reference upper limit.”

Clinicians should also bear in mind:

Borderline TSH elevation has been shown to portend deleterious impacts on various pregnancy outcomes. In the present study, we found that the higher the preconception TSH, the higher the incidence of adverse pregnancy outcomes. This was concordant with other studies, although they measured TSH during pregnancy, rather than before conception. Thyroid hormones themselves directly affect foetal development and utero-placental maturation; hence, maternal hypothyroidism can influence pregnancy outcomes, especially in early gestation.”

Regarding case management, the authors conclude:

“…preconception high TSH levels were associated with a small but significant increased risk of overall adverse events, including preterm birth, CS delivery and LGA infants, even within normal nonpregnant range. TSH <2·5 mIU/l is more suitable for the assessment of women planning a pregnancy in China, but one should not make a hasty decision to initiate treatment at this point without repeating TSH measurement and checking TPO antibody status. Prospective randomized controlled trials examining the role of levothyroxine supplement in mildly hypothyroid prepregnant women are warranted in the future.”

See also Subclinical hypothyroidism in pregnancy.

Cytomegalovirus: neglected problem endangers pregnant women, children

Medscape Cytomegalovirus

Cytomegalovirus (CMV) hasn’t gotten the press accorded to Zika, yet it infects 2%-4% of pregnant women and is transmitted to the fetus. The resulting congenital infection in 40% of these cases can result in a host of serious problems that include brain maldevelopment and microcephaly. An article recently published in Medscape Family Medicine draws needed attention to his common but poorly recognized hazard.

“Congenital CMV is well recognized as a common, endemic congenital infection, infecting over 30,000 newborns each year in the United States. Although many newborns congenitally infected with CMV may have no symptoms or sequelae, up to 8000 each year will have in utero growth restriction; petechiae; liver and spleen disease; thrombocytopenia; congenital and progressive hearing loss; vision loss; brain maldevelopment syndromes; microcephaly; and permanent neurodevelopmental and motor disabilities such as cerebral palsy. In addition, fetal and neonatal death from in utero CMV occurs in approximately 400 babies each year.”

Cytomegalovirus awareness is low

Most people have heard of Zika but very few are aware of cytomegalovirus though it is a far more widespread problem.

“…despite this well-recognized and well-accepted public health impact, only 9%-15% of women of childbearing age, including those with graduate degrees and those entering medical school, have even heard of CMV.”

“CMV Knowledge Vaccine”

Just knowing that cytomegalovirus is a common infection and serious hazard in pregnancy is the start. Then there are three simple precautions based on the fact that young children commonly excrete CMV in their saliva and/or urine for a year and transmit it to their parents 45-53% of the time, often without either manifesting any symptoms. The paper cites three recommendations to reduce exposure:

  1. Not sharing food, drink, straws or eating utensils with young children;

  2. Not kissing young children on or around the mouth or lips; and

  3. Washing hands well after changing all diapers (wet with urine or dirty with stool) and wiping runny noses or mouth drool.

Unfortunately, the American College of Obstetrics and Gynecology (ACOG) has not supported active education of women about CMV risk. The author concludes:

The greatest risk reduction strategy available now to prevent CMV transmission to pregnant women is education about CMV. Patients; healthcare professionals, especially obstetricians and midwives; and public health agencies should be partners in providing women with factual information and allowing them to make informed choices regarding their pregnancy health and prevention of CMV. In other words, spread the word, not the virus.”

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

Thyroid autoimmunity and iron deficiency in pregnancy

European Journal of Endocrinology on thyroid autoimmunity in pregnancyThyroid autoimmunity and iron deficiency are both common in pregnancy, posing a risk for numerous adverse fetal and maternal outcomes, including miscarriage. A clinical study just published in the European Journal of Endocrinology the important connection between thyroid autoimmunity and low iron, both of which can be recognized at an early stage. The authors state:

“Thyroid disorders and iron deficiency (ID) are associated with obstetrical and fetal complications. Iron is essential for the normal functioning of thyroid peroxidase (TPO-abs) and ID is frequent during pregnancy. The aim of this study was to compare the prevalence of thyroid autoimmunity (TAI) and dysfunction during the first trimester of pregnancy in women with and without ID.”

They measured ferritin to determine iron status, TPO-abs (thyroid peroxidase antibodies) for thyroid autoimmunity, and thyroid-stimulating hormone (TSH) and free T4 (FT4) thyroid function. Note that their definitions for iron deficiency (ID) and thyroid autoimmunity (TAI) were extremely ‘generous’ with ID defined as ferritin <15µg/L and TAI as TPO-abs >60kIU/L. Practitioners in this country should also note their definition of subclinical hypothyroidism (SCH) as TSH was >2.5mIU/L.

Thyroid autoimmunity and iron deficiency are common

Their data also demonstrated a significant coupling between the two:

ID was present in 35% of women. Age and BMI were comparable between both groups. In the ID group, the prevalence of TAI and SCH was significantly higher, compared with that in the non-ID group (10% vs 6% and 20% vs 16% respectively). Ferritin was inversely correlated with serum TSH and positive with FT4 levels. In the logistic regression model, ID remained associated with TAI after correction for confounding factors. The association with SCH was absent after correction for the confounders in the logistic regression model, but remained present in the linear regression model.”

MedscapeMedscape Medical News comments on these findings:

“While previous studies have indicated that iron deficiency during pregnancy can affect from 24% to 44% of women, this is the first to show the secondary effect of an increased prevalence of thyroid autoimmunity.”

Thyroid autoimmunity poses serious maternal and fetal risks. Also stated in Medscape:

“Senior author Kris G Poppe, MD, PhD, head of the Endocrine Clinic, University Hospital CHU St-Pierre, Brussels, Belgium, told Medscape Medical News that this finding is important because thyroid autoimmunity in pregnant women increases the risk of miscarriage, preterm delivery, and low birth weight compared with unaffected women.”

For important points on the multiple adverse affects of thyroid autoimmunity on pregnancy and the neonate see the earlier post Subclinical hypothyroidism in pregnancy. Standard of care for pregnancy planning and management should always include testing ferritin, thyroid antibodies and function.

The authors conclude:

ID was frequent during the first trimester of pregnancy and was associated with a higher prevalence of TAI, higher serum TSH, and lower FT4levels.”

Breast cancer recurrence reduced by prolonged nightly fasting

JAMA Oncology breast cancer and prolonged nightly fastingBreast cancer risk and prognosis is affected by glucose and insulin regulation. The authors of a study recently published in JAMA Oncology demonstrate that fasting intermittently by extending the overnight fast between dinner the night before and eating the next day reduces the risk of cancer recurrence. They state:

“To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.”

So they set out to…

“…investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep.”

Breast cancer and HgbA1c reduced by prolonged nightly fasting; sleep improved

They analyzed data collected over 12 years for 2413 women with breast cancer but without diabetes aged 27 to 70 years at diagnosis who were participants in the Women’s Healthy Eating and Living study. Their main outcomes were recurrence, new primary tumors, mortality, assess concentrations of hemoglobin A1c and C-reactive protein. Happily their data show significant improvements in recurrence, HgbA1c and sleep duration:

“The cohort of 2413 women reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality or a statistically significant higher risk of all-cause mortality. In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels and a longer duration of nighttime sleep.”

Intermittent fasting

The two most main methods of intermittent fasting are 5:2 and 16:8. 5:2 is 5 days of normal eating alternating with two very low calorie days (500 cal for females and 600 cal for males). 16:8, which I prefer, delays eating and drinking anything other than water, coffee or tea (black) until 16 hours after dinner the night before. This has numerous metabolic and immune benefits, and should be a mainstay in the ‘oncology toolbox.’ The authors conclude:

Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.”

Postmenopausal vaginal atrophy relieved by fennel cream

Maturitas[See below for update on fennel and menopausal symptoms in general.] The irritation, dryness, itching and dyspareunia (painful intercourse) of postmenopausal vaginal atrophy can be relieved by fennel cream without side effects as demonstrated by research recently published in (Maturitas, The European Menopause Journal). The authors state:

“Vaginal atrophy is one of the main concerns of postmenopausal women. The aim of the present study was to investigate the effect of fennel vaginal cream on vaginal atrophy in postmenopausal women …”

Their study cohort was divided into two equal groups, one of whom received a fennel (Foeniculum vulgare) 5% vaginal cream and the other a placebo cream. These were administered once per day for 8 weeks. Vaginal atrophy symptoms was measured at the beginning and again at 2, 4, and 8 weeks; and vaginal pH and the maturation vaginal index (MVI) were measured at the start and at 8 weeks. The fennel cream performed remarkably well:

The number of superficial cells increased significantly in the fennel group after 8 weeks compared to the control group (76.1 ± 15.3 vs. 11.8 ± 8). The number of intermediate and parabasal cells decreased significantly in the fennel group compared to the control group. The vaginal pH decreased significantly at the 8-week follow-up in the fennel group compared to the control group (100% vs. 7.4%). All women in the fennel group had an MVI of 65–100 at the 8-week follow-up, whereas almost half (40.7%) of the women in the control group had an MVI of 50–64.”

Quoted in Medscape Medical News, Dr. Parvin Abedi from Ahvaz Jundishapur University of Medical Sciences, Ahvaz stated:

The most exciting results were improving the vaginal maturation index and vaginal atrophy. Dyspareunia was improved also in participants. Since Iranian postmenopausal women do not accept the hormone therapy because of its potential risk factors, using fennel will be a good alternative for them…”recommendation for using fennel less frequently needs more evidence-based research. However, we think that it will be work if women use it for 8 weeks and then reduce the usage to 2-3 times a week.”

The authors of this welcome research paper conclude:

“According to results of this study, fennel is an effective means to manage the symptoms of vaginal atrophy in postmenopausal women and is devoid of side effects.”

Update on fennel and menopause: benefit for general menopausal symptoms

Fennel improves menopausal symptoms in generalA study just published in the journal Menopause offers further evidence that fennel can be effective for menopausal symptoms in general. In a triple-blind, placebo-controlled trial, 90 postmenopausal women were randomly assigned to treatment with soft capsules containing 100 mg fennel or placebo. The Menopause Rating Scale (MRS) questionnaire was used to assess changes in menopausal symptoms at the start; and at 4, 8, and 10 weeks after. The fennel treatment performed very well:

“The groups recorded similar mean scores on the MRS questionnaire before intervention. After intervention, the treatment group showed a significant decrease in the mean MRS score. The results of the Friedman test showed significant differences between the mean score at baseline and those at 4, 8, and 10 weeks after onset of intervention in the treatment group, whereas there were no significant differences in the placebo group. When the fennel and the placebo groups were compared, the independent t test showed significant differences in mean scores between groups at 4, 8, and 10 weeks (2 weeks postintervention).

The authors conclude:

Fennel is an effective and safe treatment to reduce menopausal symptoms in postmenopausal women without serious side effects.”

Silicone breast implants and risk of lymphoma

Journal of AutoimmunitySilicone and possibly other substances used in the manufacture of breast implants can stimulate a chronic inflammatory reaction by the immune system. A paper just published in the Journal of Autoimmunity reviews evidence that the immune reaction to silicone in breast implants can promote the development of lymphoma. The authors note:

“The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren’s syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein–Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1).”

Silicone implants stimulate an immune reaction

“A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma.”

These key points emerge:

  • Chronic infection and inflammation have been implicated as the causative mechanisms in the development of lymphomas.
  • The connection between ALCL and breast implants has been hypothesized for several years. Since the earliest report in 1997, numerous cases were described, with 173 cases of breast-implant associated ALCL being recently reported.
  • An immune reaction to silicone or other substances used in manufacturing process of breast implants, might cause T cell infiltration with later clonal expansion of T lymphocytes. The T-cell response may be as well reaction to biofilms.
  • Skin injuries and Sjögren’s syndrome are two conceptual models providing intriguing insight to the connection between silicone implants and ALCL.

Patients with silicone breast implants should be monitored

Practitioners should keep in mind the authors’ conclusion and evaluate patients with silicone implants for chronic inflammation:

“We suggest that patients with an inflammatory response against silicone implants be monitored carefully.”

Breast cancer, autoantibodies and autoimmune inflammation

BMC CancerChronic inflammation is a contributing cause for many cancers, and research recently published in BMC Cancer presents evidence that autoimmune inflammation may contribute to breast cancer by demonstrating the presence of autoantibodies directly involved in breast cancer development.

Similarities between breast cancer and autoimmune diseases

The authors state:

“Our studies on autoantibodies in malignancies strongly suggested that cancer sera exhibit immunologic features that are common in the rheumatic autoimmune diseases [ADs]. We have shown that anti-collagen antibodies and antinuclear antibodies [ANA] are found in the sera from lung cancer and head and neck cancer patients as frequently as in the systemic ADs such as rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]. With the use of molecular techniques and high throughput analyses, we and others have clearly shown that autoantibody classifiers have been constructed with high sensitivity and specificity for the diagnosis of breast and other cancers.”

Predictive antibodies

Autoantibodies can appear years before the condition evolves to an easily recognized clinical entity.

“It is well known that autoantibodies (such ANAs in SLE and rheumatoid factors and anti-cyclic citrullinated peptides antibodies in RA) can be detected many years before the onset of these ADs. We and others have also found autoantibodies in the sera of patients with cancer before clinical diagnosis, notably suggesting that the breakdown of tolerance to tumor antigens is an early event in carcinogenesis. The diagnostic value of autoantibodies as immune biomarkers in the systemic and organ-specific ADs such as SLE, RA, scleroderma, and primary biliary cirrhosis [PBC] is well established.”

Although anti-nuclear antibodies (ANAs) have been recognized in breast cancer sera for many years there has been no comprehensive study of autoantibodies in the sera of a large cohort of patients with pathology-proven breast cancer. So…

“The objective of this work was to demonstrate that the autoantibodies detected in BC sera have unique immunological features, resembling the model epitomized by the rheumatic and organ-specific ADs.”

Autoantibodies clearly apparent in breast cancer

They used immunofluorescence on HEp-2 cells to survey autoantibodies in sera from women undergoing annual screening mammography with suspicious assessment and immunoblots of breast cancer proteins, crithidia luciliae assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens [ENAs], anti-centromere antibodies [CENPs], and NSP1 antibodies and for the M2 component of pyruvate dehydrogenase. These included sera from 100 cases each of ductal carcinoma in situ [DCIS], invasive ductal carcinoma [IDC] of the breast and controls of benign breast disease [BBD]. The pathologic diagnoses of cases were made by breast biopsy. Autoantibodies were clearly present in the subjects with breast cancer:

“The combined use of IFA [immunofluorescence] on HEp-2 cells and IBs [immunoblots] of BC [breast cancer] proteins detected autoantibodies in virtually all sera from patients with breast cancer. IFA of BC and control sera revealed a spectrum of autoantibodies with maximal reactivity in sera from patients with IDC and decreasing reactivity in DCIS and BBD sera; minimal nuclear or cytoplasmic reactivity was shown in the sera from patients with OA and from healthy hospital nurses.”

Moreover, they showed that autoantibodies in breast cancer sera have unique immunological features comparable to those found in rheumatic and organ-specific autoimmune diseases.

“We show here that autoantibodies reacting with antigens located in several important cell organelles (including mitochondria, centromeres, nucleoli, centrosomes, and the mitotic spindle) are consistently found in sera from women with suspicious mammography findings. The level of these autoantibodies was highest in women with IDC, lesser in women with DCIS, and still lower but above background levels in healthy women with BBD. Moreover, AMAs, anti-centromere, and anti-centrosome antibodies are not components of the autoantibody repertoire of normal healthy women.”

Clincial implications for diagnosis and prevention of breast cancer

The authors note the diagnostic utility of breast cancer antibody profiles:

“These findings suggest that, in the future, the combination of suspicious mammography and autoantibody signatures could potentially identify a group of women in the early stages of breast carcinogenesis. Here we provide evidence that most of the antigens targeted by autoantibodies in BC sera differ from those involved in the rheumatic and organ-specific ADs.”

Although autoantibodies and other screening methods are superseded by the ONCOblot test, this report is a valuable reminder for clinicians to thoroughly attend to low grade chronic inflammation and early stages of autoimmunity as a fundamental tactic in breast cancer prevention.

Moreover, considering the current controversy regarding justification and potential harm associated with radical treatment of DCIS, investigating and treatment underlying autoimmune inflammatory factors presents a middle option between invasive therapy and doing nothing.

The authors conclude:

“In this study, detection of autoantibodies in the sera from practically all women with breast cancer provides compelling evidence that an antigen-driven autoantibody response takes place in BC. Moreover, we report here that the autoantibody profile detected in BC sera has distinctive features, probably reflecting unique BC-associated antibody specificities targeting antigens in the mitochondria, the centrosomes, the spindle apparatus, the nucleoli, and the cytoskeleton.”

Furthermore…

“The consistent finding of anti-centrosome antibodies in breast cancer sera is novel and supports the possibility that centrosome autoimmunity might be involved in cancer pathogenesis. Detection of AMAs, anti-centromere, anti-centrosome antibodies, and MNDs in a fraction of women with suspicious mammography findings and BBD indicates that the process triggering autoantibody formation starts in the pre-malignant phase. Our findings suggest the hypothesis that autoimmunity triggered by TAAs may inflict epithelial damage to the breast, promoting chronic inflammation and cancer progression; i.e., that BC may behave as an organ-specific AD triggered by multiple epithelial and other breast antigens.”

Allergic inflammation may promote breast cancer metastasis

Journal of Leukocyte BiologyIt’s well known that inflammation contributes to ‘flipping the molecular switches’ that turn on breast cancer and other malignancies. A study entitled Allergen induced pulmonary inflammation enhances mammary tumor growth and metastasis: Role of CHI3L1 recently published in the Journal of Leukocyte Biology reveals a mechanism by which allergic inflammation can promote breast cancer metastasis. The authors state:

“Metastasis is the primary cause of mortality in women with breast cancer. Metastasis to the lungs is greater in patients with pulmonary inflammatory illnesses. It is unknown how pre-existing pulmonary inflammation affects mammary tumor progression. We developed a novel breast cancer model in which pulmonary inflammation is induced in mice prior to tumor cell implantation.”

CHI3L1 associated with allergic inflammation promotes breast cancer metastasis

They had earlier shown that a glycoprotein known as CHI3L1 associated with lung inflammation induces the production of proinflammatory and protumorigenic molecules. Here they show how allergic inflammation alters the lung environment to promote breast cancer metastasis.

“In the present study, we determined how pre-existing allergen-induced inflammation changes the pulmonary microenvironment to exacerbate tumor metastasis. We showed that pre-existing pulmonary inflammation in mammary tumor bearers is associated with: 1) an increase in growth of the primary tumor and metastasis; 2) an increase in the expression of a glycoprotein known as CHI3L1; and 3) increase in the levels of myeloid populations in their lungs. We also showed that myeloid derived cells from the lungs of allergic tumor bearers produce higher amounts of CHI3L1 than the saline controls.”

They further demonstrated the key role of CHI3L1 by removing the glycoprotein from the picture:

“In this study, we show that CHI3L1 knockout tumor bearers with pre-existing allergic pulmonary inflammation had decreased levels of myeloid-derived cells, decreased levels of proinflammatory mediators, and a significant reduction in tumor volume and metastasis compared with the wild-type controls.”

Targeting allergic inflammation in breast cancer

The authors conclude with a comment on the clinical importance of targeting allergen-induced inflammation in breast cancer management:

Pre-existing inflammation and CHI3L1 might be driving the establishment of a premetastatic milieu in the lungs and aiding in the support of metastatic foci. Understanding the role of allergen-induced CHI3L1 and inflammation in tumor bearers and its effects on the pulmonary microenvironment could result in targeted therapies for breast cancer.”

Breast cancer, oxidative stress and NF-κB

Breast Cancer Research and TreatmentA paper just published in the journal Breast Cancer Research and Treatment highlights how reactive oxygen species (ROS) activate pro-inflammatory NF-κB (nuclear factor kappa beta, also an oncogenic transcription factor) to promote more aggressive breast cancer, and that this can be ameliorated by N-acetyl-cysteine. The authors state:

Reactive oxygen species (ROS) are thought to be among the initiating insults that drive carcinogenesis; however, beyond the mutagenic properties of ROS, it is unclear how reactive oxygen species and response to redox imbalance may shape cancer phenotype.”

DNA damage-responsive kinase ATM turns on NF-κB

They demonstrate that oxidative damage to DNA activates the kinase ATM which in turn revs up the tumor-promoting and inflammatory NF-κB:

“We have previously observed that basal activity of the powerfully oncogenic transcription factor NF-κB in cultured breast cancer and other tumor cell lines is dependent upon the DNA damage-responsive kinase ATM. Here we show that, in MDA-MB-231 and HeLa cells, basal ATM-dependent NF-κB activation occurs through a canonical DNA damage-responsive signaling pathway as knockdown of two proteins involved in this signaling pathway, ERC1 and TAB1, results in loss of NF-κB basal activity. We further show that knockdown of ATM in MDA-MB-231, a breast cancer line with a pronounced mesenchymal phenotype, results in the reversion of these cells to an epithelial morphology and gene expression pattern.”

In other words, by removing ATM from the chain prevents NF-κB from converting cells to the worse breast cancer phenotype.

N-acetyl cysteine (NAC) to the rescue

Clinicians involved in case management of autoimmune disorders are aware that N-acetyl cysteine (NAC) is one of the beneficent agents that help wind down NF-κB activity (a major player also in autoimmune inflammation). Here the authors show that NAC prevents NF-κB from turning on more harmful breast cancer genes:

“Culture of MDA-MB-231 and HeLa cells on the antioxidant N-acetyl cysteine (NAC) blunted NF-κB transcriptional activity, and long-term culture on low doses of NAC resulted in coordinate reductions in steady-state ROS levels, acquisition of an epithelial morphology, as well as upregulation of epithelial and downregulation of mesenchymal marker gene expression. Moreover, these reversible effects are attributable, at least in part, to downregulation of ATM-dependent NF-κB signaling in MDA-MB-231 cells as RNAi-mediated knockdown of the NF-κB subunit RelA or its upstream activator TG2 produced similar alterations in phenotype.”

Clinical note

Practitioners involved in breast cancer prevention and treatment should be attentive to patients’ oxidative status which can be quantified with biomarkers such as the DNA oxidation product 8-Hydroxy-2-deoxyguanosine, and have practical familiarity with NAC and other agents that reduce ROS to acceptable levels and rein in NF-κB. The authors summarize:

“We conclude that chronic activation of ATM in response to persistent ROS insult triggers continual activation of the oncogenic NF-κB transcriptional complex that, in turn, promotes aggressive breast cancer phenotype.”