A feature of neoplastic cells is that mutations in the key intermediates of TGF-β signaling contribute to the loss of sensitivity to its anti-tumor effects. The role of SMAD3 and SMAD4 germline mutations in breast cancer predisposition is currently unclear. To address this, mutation analysis of the Mad-Homology 2 domains in 408 breast cancer cases and 710 controls recruited by the Breast Cancer Family Registry (BCFR) was performed using Denaturing High-Pressure Liquid Chromatography. This study identified 23 distinct intronic variants, and three coding variants c.1214T>C, c.1478G>A, and c.1701A>G in SMAD4. No aberrant splicing was observed, but qPCR analysis and tissue expression data showed significantly elevated SMAD3 expression relative to controls (p<0.05). For SMAD4, c.1478G>A from a familial breast cancer case showed a 5-fold expression change. Taken together, inactivating alterations are not driving tumorigenesis. Rather, aberrant germline expression provides novel insight into SMAD3 and SMAD4’s roles in breast cancer predisposition.

Folate intake in North America has drastically increased over the past decade due to folic acid fortification and widespread supplemental use. The role of folate in breast cancer is highly controversial and the effects of folic acid supplementation on breast cancer patients are currently unknown. An animal study was performed to determine the effects of folic acid supplementation on the progression of the mammary tumors in the DMBA-carcinogen model. Folic acid supplementation was associated with more rapid sentinel tumor progression and with higher sentinel tumor weight, volume, and area, although no clear dose-responsive relationship was observed. Folic acid supplementation was associated with an increased expression of proapoptotic protein PARP and decreased expression of proliferation protein PCNA. These data suggest that folic acid supplementation may promote the progression of established mammary tumors. Whether or not folic acid supplementation may adversely affect the outcome of patients with breast cancer warrants further studies.

Epithelial-mesenchymal transition (EMT) has a critical role in tumor progression and has been correlated with the basal-like subtype of human breast cancers. Here I report a novel β-catenin binding protein, which I have shown to be expressed in invasive breast cancer and hypothesized to have a role in breast tumor progression. In normal breast tissue, expression is restricted to the myoepithelium while in breast cancer the expression pattern is similar to smooth muscle actin and vimentin. I have demonstrated that silencing of this protein in breast tumor cells reduces migration by over 50 percent. Furthermore, I have identified this β-catenin binding protein as a target of the Snail EMT network and have demonstrated this protein to be a marker of basal-like carcinomas. These results define a role for this novel protein in EMT, as a marker for the basal subtype, and a promising therapeutic target for metastasis inhibition.

It has long been known that vitamin D is important for calcium absorption and bone health. More recently, vitamin D has been found to modulate breast cancer cell growth and increasingly epidemiologic studies suggest vitamin D may be associated with reduced breast cancer risk. The primary objective of this thesis was to evaluate the associations between vitamin D from all sources (food, supplements and sunlight exposure) and breast cancer. Secondary objectives were focused on methodological issues including the development of a solar vitamin D score and adapting the measurement of vitamin D from foods for use among Canadians. The data source for this study was the “Ontario Women’s Diet and Health Study”, a population-based case-control study of women in Ontario. Cases (n = 3,101) diagnosed between 2002 and 2003 were identified through the Ontario Cancer Registry and controls (n = 3,471) were identified through random digit dialing of Ontario households. Study participants completed mailed risk factor and food frequency questionnaires. Vitamin D intake from supplements (>400 IU/day compared to none) was found to be associated with reduced breast cancer risk (OR = 0.76; 95% CI: 0.59, 0.98). However, total vitamin D intake (from food and supplements) and intake from food alone were not associated with breast cancer risk. Time spent outdoors during 4 periods of life (including adolescence) was associated with reduced breast cancer (e.g., highest versus lowest categories of exposure at age 40 to 59: OR = 0.74; 95% CI: 0.61, 0.88). The novel solar vitamin D score, derived from time spent outdoors, skin color, sun protection practices, and ultraviolet radiation of residence, was also associated with reduced breast cancer risk. In summary, there is some evidence to suggest that vitamin D intake from supplements and determinants of cutaneous vitamin D production are associated with reduced breast cancer risk.

Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance. This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. A constructed interactome suggested that there is cross-talk at the Nrf-2 oxidative stress pathway between genes associated with resistance to doxorubicin and paclitaxel. This unique GWA approach serves as a proof-of-principle study and systematically investigates targets responsible for variable response to chemotherapy in breast tumor cells and possibly the tumors of breast cancer patients. Overall, the model discovered novel candidate genes that have not been previously associated with doxorubicin and paclitaxel cytotoxicity. Future studies will be directed at illustrating a causative relationship between the observed genomic changes and drug resistance in breast cancer patients undergoing doxorubicin and paclitaxel chemotherapy.

BACKGROUND: Breast cancer patients typically present with unhealthy body composition (high fat mass and low muscularity) near diagnosis. These body composition characteristics often worsen during treatment and ultimately contribute to the development of secondary diseases like diabetes and cardiovascular disease in survivorship. Inflammation in overweight or obese individuals is associated with impaired glucose metabolism; the presence of the tumour may lead to greater impairments in glucose metabolism in breast cancer patients. OBJECTIVES AND HYPOTHESES: The objectives of this study were to: 1) evaluate breast cancer patients near the onset of treatment for metabolic measures including an oral glucose tolerance test (OGTT), cytokine profiles, as well as body composition, nutritional status and fitness and, 2) make comparisons between breast cancer patients, age- and BMI-matched females (HM females), and a group of young, non-malignant females with healthy BMIs (HY females) on these measures. We hypothesized that breast cancer patients would demonstrate impaired glucose metabolism relative to HM females, and that this would be attributed to systemic inflammation. We also hypothesized that both breast cancer patients and HM females would present with unhealthy body composition, impaired glucose and lipid metabolism, systemic inflammation, poor fitness and greater caloric intake compared to HY females. METHODS: We evaluated body composition using % body fat (skinfold callipers) and waist circumference. Following collection of fasting blood samples, an OGTT was conducted to assess glucose, insulin, c-peptide and glucagon dynamics. Fasting blood samples were analysed for lipids and pro- and anti-inflammatory cytokines. Incremental exercise tests were conducted to assess VO2peak, and estimated 1-RM tests assessed strength of the biceps, triceps and quadriceps muscles. Baecke and CHAMPS questionnaires provided an indication of habitual physical activity. A 3-day food record was used to analyze daily caloric intake and macronutrient distribution. Breast cancer patients and HM females were compared using paired t-tests. Patients and HM females were compared to HY females using t-tests. Statistical significance was accepted at p < 0.05. RESULTS: Overall, breast cancer patients were overweight (BMI: 28.8 ± 6.0 kg/m2) and presented with abdominal obesity (waist circumference: 94.6 ± 14.0 cm) and dyslipidemia (TAG: 1.84 ± 1.17 mM and HDL-c: 1.08 ± 0.23 mM), indicating risk for metabolic syndrome. Although fasting glucose concentrations did not differ between the 3 groups, breast cancer patients demonstrated higher glucose concentrations at 30 min during an OGTT. Similar to glucose, fasting insulin concentrations did not differ between the 3 groups, but patients demonstrated higher insulin at 150 min during an OGTT. Breast cancer patients had elevated fasting serum c-peptide (2.6 ± 1.2 ng/mL vs. 1.9 ± 0.8 ng/mL, p = 0.005). C-peptide remained elevated in patients compared to non-malignant females during the last hour of the OGTT, indicating that insulin secretion was sustained in breast cancer patients. We observed no difference in serum cytokines between patients and HM females or between patients and HY females. VO2peak, although lower compared to HY females, was similar in patients and HM females. There were no differences in habitual physical activity or nutrition measures between any groups. DISCUSSION AND CONCLUSIONS: Breast cancer patients presented with poorer glucose features during an OGTT compared to HM and HY females. However, systemic inflammation, body composition, energy expenditure and energy intake were similar in breast cancer patients and HM females. Thus, these impairments may be tumour-related. Future studies need to specifically elucidate the effects of the tumour in host glucose metabolism.

It is commonly believed that breast cancer dragon boating benefits survivors in a range of psychosocial areas, but there have been few empirical studies to investigate such relationships. An interpretive description design and a critical health promotion approach were used to explore the psychosocial experiences of women who breast cancer dragon boat. In-depth interviews with six participants were analyzed. Themes that arose from the data are: (1) moving past isolation — networks of like-minded support, (2) taking control,(3) journey into adventure, (4) affirmative outlook, (5) confronting painful experience, (6) rebuilding identity, (7) and spiritual engagement. The findings illustrate that dragon boating provides breast cancer survivors with a significant venue for change and the opportunity to move beyond traumatic elements of cancer.

Monoamine oxidase-A (MAO-A) is an enzyme that has historically been linked to major depressive disorder (MDD). The prevalence of MDD among breast cancer patients is almost 25%, but realistically it is underdiagnosed within this patient population. Most breast cancer is deemed estrogen receptor positive [ER(+)] and is commonly treated with the anti-estrogenic chemotherapeutic compound tamoxifen. Resistance to tamoxifen has been associated with a paradoxical activation of the stress-associated kinase, p38(MAPK) (normally associated with cell death). Our research group has recently demonstrated that p38(MAPK) can regulate the function of MAO-A in glial cells. Taken together, MAO-A, depression and p38(MAPK) are all associated with a poor prognosis in breast cancer patients, particularly those with an ER(+) status. Several mechanisms have been proposed in each respect and we hope to further elucidate this relationship by focussing on the interaction between MAO-A and p38(MAPK) in the context of breast cancer. The hypothesis states that a functional interaction between the p38(MAPK) and MAO-A systems alters breast cancer cells in an ER-dependent manner. The proposed objectives of this project are to determine what might be influencing MAO-A function in breast cancer cells, and how changes in MAO-A function affect cell phenotype. Using pharmacological approaches (i.e. antidepressant drugs), we investigated the role of MAO-A and p38(MAPK) on selected characteristics of ER(+) (e.g. MCF-7) and ER(-) (e.g. MDA-MB-231) breast cancer cells under four treatment conditions, which include clorgyline (CLG), an antidepressant MAO-A inhibitor, and SB203580, an inhibitor of p38(MAPK). Our results indicate that the very high MAO-A activity in MDA-MB-231 (MB-231) cells was partly dependent on p38(MAPK) activity. The tumourigenic properties (e.g. anchorage-independent growth, migration) of MB-231 cells depended on both MAO-A and p38(MAPK) functions, although the effects were not additive suggesting that both inhibitors were exerting their respective effects via common signalling targets. The role of MAO-A and p38(MAPK) on MB-231 mitochondrial function and cell growth was negligible. In contrast, MAO-A and p38(MAPK) only influenced mitochondrial function in MCF-7 cells and did not affect any of the other tumourigenic properties measured. Immunocytochemical methods, supported by Western blotting, revealed an increase in E-cadherin expression in both cell lines. This suggested that MAO-A and p38(MAPK) could be influencing transitions between epithelial and mesenchymal phenotypes. Our in vitro findings suggest that MAO-A and p38(MAPK) might contribute to a common mechanism in breast cancer cell lines, but that their influence on cell phenotype is less dependent on the respective cell's ER status and perhaps more so dependent on the cell's metastatic potential. If this is the case, then the contribution of MAO-A and p38(MAPK) to [clinical] metastatic breast cancer should be duly considered. Our ongoing investigations are focussing on the influence of clinically relevant antidepressants on breast cancer cell phenotype in vitro.

Bakgrund: I Sverige diagnostiseras årligen cirka 40 män med bröstcancer. Det är en sjukdom som ofta associeras med kvinnor vilket resulterar i en okunskap där många inte är medvetna om att även män kan drabbas. Endast ett fåtal kliniska studier är utförda på män vilket leder till att de erbjuds behandling efter samma riktlinjer som kvinnor.  Syftet: Syftet var att belysa förekomsten av bröstcancer hos män samt deras upplevelser av att ha sjukdomen. Metod: En allmän litteraturstudie baserad på vetenskapliga artiklar genomfördes. Resultat: Resultatet visade att männen var chockade över att ha fått diagnosen bröstcancer. De uppfattade det som en könsrelaterad sjukdom och ville inte avslöja sin diagnos för omgivningen. Generellt var männen besvikna över informationen som de erhållit då den endast var fokuserad på kvinnor. Deltagarna fick även en förändrad kroppsuppfattning till följd av att de genomgått en mastektomi. De upplevde att deras maskulinitet och sexualitet ifrågasattes. Diskussion: Utifrån resultatets fynd fördes en diskussion kring det kvinnliga fokuset, en förändrad kroppsuppfattning och bristen på kunskap. Slutsats: Denna studie visar att ytterligare forskning krävs för att öka medvetenheten kring bröstcancer hos män. Sjuksköterskan bör ha förståelse och kunskap om hur män upplever sjukdomen. / Background: In Sweden approximately 40 men each year are diagnosed with breast cancer. It is a disease that often is associated with women. Only a few clinical studies are based on men with the result that they are offered treatment following the same guidelines as women. The aim: The aim was to elucidate the incidence of breast cancer in men and their experiences of having the disease. Methods: We conducted a general literature study based on scientific articles. Results: The results showed that the men were shocked at having been diagnosed with breast cancer. They perceived it as a gender-related illness and did not want to disclose their diagnosis to their surroundings. Generally, the men were disappointed with the information made available to them. Participants also had an altered body image due to the mastectomy. They felt that their masculinity and sexuality was questioned. Discussion: Based on the findings in the result there was a discussion on the feminine focus, an altered body image and the lack of knowledge. Conclusion: This study shows that further research is needed to raise awareness of breast cancer in men. The nurse should have an understanding and knowledge of how men experience the disease.

Syftet med denna systematiska litteraturstudie var att beskriva de psykosociala och existentiella behov som kan uppstå hos kvinnor med bröstcancer samt i hur stor utsträckning bröstcancerpatienter upplever att dessa behov tillgodoses i vården. Dessutom var syftet att få en uppfattning om betydelsen av komplementär och alternativ medicin för bröstcancerdrabbade kvinnor. De vetenskapliga artiklar (n=25) som ingick i studien söktes datoriserat samt manuellt och en kvalitetsgranskning gjordes av litteraturen utifrån olika bedömningsformulär. Resultaten visar att de behov som uppstod hos kvinnorna med bröstcancer var behov av stöd, behov av information samt behov av kontinuitet i sjukvården. Majoriteten av kvinnorna upplevde att det psykosociala och existentiella stödet i sjukvården samt den information de fick hade stora brister. Detta ansågs i stor utsträckning bero på en bristfällig kontinuitet. De komplementär- och alternativmedicinska behandlingarna visade sig vara mycket betydelsefulla då de i stor utsträckning tillgodosåg de psykosociala och existentiella behoven hos bröstcancerpatienterna. Behandlingarna minskade psykiska symtom som oro, ångest och depression avsevärt hos kvinnorna samt hjälpte dem att hantera och bearbeta känslor förknippade med cancerdiagnosen och nå ett accepterande av sin sjukdom. Kontinuiteten upplevdes dock ibland som bristfällig även inom den komplementär- och alternativmedicinska vården.