Flaxseed oil (FO), rich in α-linolenic acid, has been shown to inhibit breast cancer growth. One suggested mechanism is through modulation of HER2 expression and signalling. This study determined the effect of FO on the growth of established HER2-overexpressing breast tumours (BT-474) and its interaction with two doses of a primary anti-HER2 therapy, trastuzumab (TRAS), in athymic mice. FO alone had no effect on tumour size, cell proliferation and apoptosis. TRAS (2.5 and 5 mg/kg) reduced tumour size and cell proliferation but had no effect on apoptosis. TRAS (2.5 mg/kg) combined with FO reduced tumour size and cell proliferation and increased apoptosis compared to TRAS (2.5 mg/kg) alone and was just as effective as 5 mg/kg TRAS. TRAS (5 mg/kg) resulted in almost complete tumour regression with or without FO. In conclusion, FO has no effect on BT-474 tumour growth but can enhance the effectiveness of low dose TRAS.

The human Fyn-related kinase (FRK) is a member of subfamily of Src-related kinases family. FRK is 54 kDa non-receptor tyrosine kinase protein composed of 505 amino acids. FRK consists of three functional domains: Src homology 3 (SH3), SH2 and kinase domain, as well as a putative tyrosine kinase regulator at the C-terminus. FRK has a conserved auto-regulatory tyrosine residue within its kinase domain. It has been reported that FRK is repressed in about 30 % of human breast cancer samples. Over-expression of FRK in breast cancer cells of the mammary gland was shown to suppress cell growth by interacting, phosphorylating and stabilizing the tumor suppressor PTEN, thus inhibiting AKT/PI3K signaling. Although it has been suggested that FRK is a tumor suppressor gene, the effects of activated FRK on cell proliferation, migration and invasion are unclear. Likewise, the signaling pathways regulated by the activation of FRK have not been yet fully characterized. We hypothesize that the activation of FRK is essential for the regulation of its cellular functions. Mutation of the C-terminal auto-regulatory tyrosine 497 to phenylalanine (FRK-Y497F) resulted in the constitutive activation of FRK. We generated stable cell lines expressing either the FRK wild type (FRK-WT) or FRK-Y497F from triple negative breast cancer MDA-MB-231 cells. The introduction of FRK-Y497F in MDA-MB-231 cells significantly suppressed their proliferation, migration, invasiveness and colony formation as compared to cells that expressed the FRK-WT gene. Over-expression of either FRK-WT or FRK-Y497F in MDA-MB-231 cells inhibited the phosphorylation of AKT, STAT3, JNK and P38 MAPK as compared to either the MDA-MB-231 parental cells or those that were transfected with the empty vector. Our results suggested that FRK represses cell proliferation, migration, invasiveness and colony formation at least in part by the inhibiting the activation of AKT/PI3K, JAK-STAT and MAPK signaling pathways.

No description available.

Docetaxel is a chemotherapy drug used to treat breast cancer, however as with many chemotherapeutic drugs, resistance commonly occurs and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulatory mechanisms like DNA methylation, histone deacetylation and miRNA expression have been shown to play an important role in cancer drug resistance. This study investigated the role of these mechanisms in two in vitro breast cancer cell line models (MCF-7 and MDA-MB-231) of acquired docetaxel resistance. Using inhibitors to DNA methylation and histone deacetylation, response to docetaxel could be enhanced in both breast cancer cells and cDNA microarray expression analysis identified candidate genes that were re-expressed after treatment with both inhibitors, therefore being associated with docetaxel resistance. Decreased expression of one candidate gene, SERPINE1, was directly linked to docetaxel resistance whereby SERPINE1 modulation, using siRNA technology, directly altered response to docetaxel. Furthermore, miRNA expression profiling was performed in both docetaxel-sensitive and docetaxel-resistant cell lines where alterations of miRNAs were observed and associated with a docetaxel-resistant phenotype. In particular, increased expression of miR-34a was identified in docetaxel-resistant cells, which was associated with and with decreased BCL2 and cyclin D1 mRNA and protein expression in these cells. Modulation of miR-34a expression altered docetaxel response in both docetaxelsensitive and docetaxel-resistant cells, therefore identifying increased miR-34a as direct cause of docetaxel resistance in these cells. In addition, miR-34a was shown to directly target BCL2, which may present a mechanism through which miR-34a mediates docetaxel resistance. Overall, this study identified alterations in DNA methylation, histone deacetylation and miRNA expression as mechanisms through which gene expression is altered in docetaxel-resistant breast cancer cells.

Comparative genomic hybridization has previously identified regions of genomic alteration associated with docetaxel resistance in MCF-7 and MDA-MB-231 breast cancer cell lines. Amplification of chromosome 7q and loss of chromosome 10q were two common regions of alteration in these docetaxel-resistant breast cancer cells. Loss of chromosome 12p was associated with resistance in MCF-7 cells only. In the present study, the minimal region of chromosome 12p loss was identified by BAC-fine-mapping in. Bio-informatics was used to identify candidate genes within the minimal region of alternative on chromosomes 7q, 10q and 12p. This study identified that docetaxel resistance was associated with decreased mRNA and protein expression of both transforming acidic coiled-coil protein 2 (TACC2) on chromosome 10q, and dual specificity phosphatase 16 (DUSP16) on chromosome 12p, in the MCF-7 docetaxel-resistant cell line. However, in the MDA-MB-231 docetaxel-resistant cell line, expression of TACC2 was increased at the mRNA level and decreased at the protein level whilst expression of DUSP16 was not investigated. Silencing the expression of these genes, using siRNA technology, in the docetaxel sensitive MCF-7 cell line did not make them more resistant to docetaxel. Therefore, while decreased expression of TACC2 and DUSP16 are associated with docetaxel resistance it is unlikely that these changes are causative of drug resistance in this cell line model. Furthermore, this study demonstrated that increased mRNA and protein expression of caveolin 1 (CAV1) was associated with resistance to docetaxel in the MDA-MB-231 docetaxel-resistant cell line. Decreasing CAV1 expression, by siRNA, in this cell line increased sensitivity to docetaxel. Increased expression of CAV1, therefore, may contribute, at least partially, to the mechanism of acquired resistance to docetaxel in MDA-MB-231 breast cancer cells. It is therefore imperative to confirm these results in breast cancer tissues.

Fifteen years ago, the Steroid receptor RNA activator (SRA) was identified as a functional non-coding RNA able to increase the activity of the estrogen receptor (ER), a critical player mediating the mitogenic role of estradiol in breast cancer. Interestingly, four years later, SRA appeared to be the first ever discovered functional RNA also able to encode a protein (SRAP). As such, the products of the SRA1 gene delineate a fascinating bi-faceted system involving both a functional RNA and a protein. Since its discovery, the non-coding aspect of this system has been widely investigated, with multiple groups gathering information on SRA structure and related functions. Overall, the non-coding SRA transcript is thought to act as a broad co-regulator modulating the activity of different transcription factors. Conversely, limited information has been obtained on the coding aspect (SRAP) of this system，even though SRA/SRAP is currently believed as a whole to be involved in several mechanisms including tumourigenesis, tumour progression, myogenesis and adipogenesis. In this body of work, I have attempted to define the clinical relevance of SRAP to breast cancer and extend the understanding of the cellular processes potentially regulated by this protein. I have first established that SRAP had the potential to become a new prognostic and predictive factor in specific groups of patients. Indeed, I have demonstrated, using tissue microarray analyses (TMAs), that SRAP expression was up-regulated in some breast tumours, with high levels associated with poor prognosis in Estrogen Receptor (ER) positive breast cancer patients. Using the same technique, I have further identified a positive association between a positive response to tamoxifen treatment and a high level of SRAP expression in a large cohort of ER-α negative cases. This highlights the potential for SRAP to become a new predictive factor of response to endocrine therapy in this specific group of patients. Using RNA-seq to define the transcriptomes of cervical Hela and breast MDA-MB-231 cancer cells upon depletion or overexpression of this protein, I further identified cellular movement amongst the potential cellular processes affected by changes in SRAP expression. Using classical trans-wells assays as well as an live-cell imaging assays, I have confirmed that SRAP indeed regulates individual cancer cell motility. Overall, my results provide critical new insights into the potential functions of the protein counterpart of the intriguing SRA/SRAP bi-faceted gene system. SRAP herein appears as a potential new therapeutic target in the fight against breast cancer that remains to be further investigated. / February 2017

This report describes the project background, design process plus the final result of my MFA degree thesis in Advanced Product Design at Umeå Institute of Design. A breast pump is generally a mechanical or electrical suction device for withdrawing milk from the breast of a lactating woman. Even though the first pumps were patented in the mid-19th century as medical devices for in-hospital use, breast pumps as widely available consumer products have only been around for a little more than 20 years. Existing breast pumps do not address functional as well as emotional needs of many mothers and there is great potential for improvements and innovative solutions to transform pumping into a more enjoyable and positively associated experience. The main purpose of this project is to rethink the way breast pumps are currently used in order to push the boundaries, and come up with a forward-looking, conceptual design solution as a final result. This human-centered design project was carried out in close collaboration with various experts in the areas of pediatrics, breastfeeding and lactation counselling. Moreover this project was done in cooperation with leading design and innovation consulting firm IDEO. San Francisco basted design director Thomas Overthun provided mentoring throughout the design process. Regular check-in calls and feedback sessions were set up throughout the project to discuss project milestones. Anders Smith, an experienced industrial designer from Denmark, closely followed throughout the project as an external design tutor at Umeå Institute of Design. Several tutoring sessions were held on a regular basis. Continuous involvement of experts and external project advisors helped to make sure that the project remains valid and provided a great source for relevant insights, expert knowledge and professional feedback. "Being able to develop an impactful and forward-looking design solution that can encourage positive change both on an individual and societal level has been my main motivation to tackle this design challenge".

No description available.

No description available.

Breast cancer is the most common type of female cancer in the UK and the second most common cause of cancer death. Many factors, including genetic and environmental influences, contribute to an individual's lifetime risk. The role of epigenetics, particularly DNA methylation, has been considered as a mechanism that could link these risks and provide a non-genetic explanation of cancer heritability. Loss of imprinting is a hallmark of many cancers and has been observed in non-tumour tissue of affected and at risk individuals. Many imprinted genes maintain their allele specific methylation in a wide range of adult somatic tissues, remaining stable throughout life. Repeat elements are also of interest as they have been implicated in imprint maintenance. The main hypothesis of this study was that altered DNA methylation at imprinted gene regions would be observed in blood samples of breast cancer patients, when compared to a matched disease-free population. Methylation levels of imprinted gene regions and repeat elements were examined for breast cancer risk and associated clinical and pathological characteristics, within a case-control cohort. Genotypes within the 11p15 imprint cluster (a region which presents loss of imprinting in cancer) were examined and interactions with epigenotype considered. DNA methylation changes were observed in non-tumour tissue in women with breast cancer at imprinted genes PEG3, INPP5F, KCNQ1OT1, KvDMR, L3MBTL and PLAGL1/ZAC1. Methylation changes were identified which have the potential to differentiate between patients who may or may not progress onto invasive breast cancer. Pathological characteristics of breast cancer were also linked to DNA methylation changes which could enhance our knowledge of tumour heterogeneity. Genotype-epigenotype interactions were observed within the 11p15 region and two genetic variants were associated with breast cancer risk. Results reported here enhance our current knowledge of methylation changes in blood of breast cancer patients and could contribute to the development of screening approaches and personalised treatments.