The 16α-alkylation was achieved via treatment of 3-methoxyestra-1,3,5(10)-trien-17-one-N,N-dimethylhydrazone (118) with n-butyllithium and the appropriate haloalkane to afford exclusive 16α-substitution (119). Subsequent, cupric ion-catalysed hydrolysis, 17-ketone reduction and removal of the 3-hydroxyl protecting group, furnished 16α-methylestra-1,3,5(10)-trien-3,17β-diol (122a) and 16α-ethylestra-1,3,5(10)-trien-3,17β-diol (122b). An alternative sequence to the 16α-ligands, by direct alkylation of the 17-keto-estrone enolate, was also investigated. In this manner 16α-allylestra-1,3,5(10)-trien-3,17β-diol (122c) and 16α-benzylestra-1,3,5,(10)-trien-3,17β-diol (122d) were obtained.

Breast cancer in South Africa has become one of the most prominent cancers affecting women. Worldwide, breast cancer results in more deaths amongst women than any other cancer (Vorobiof, 2001). Chemotherapy has become one of the most effective and commonly used adjuvant forms of treatment in breast cancer. However, despite its effectiveness, it has a variety of side effects ranging from nausea, fatigue, vomiting, alopecia to many others. Due to the significant levels of discomfort and disability associated with chemotherapy, patients often seek additional treatment to assist with these side effects. Many individuals combine complementary and alternative therapies with conventional treatment of their cancer (Breasthealth, 2005). Homoeopathy is often used to alleviate the side-effects resulting from the chemotherapy treatments (Diamond and Crowden, 1997). This research involved the individualized treatment of patients experiencing side effects from chemotherapy, employing homeopathic medicine. The study involved ten participants who had been diagnosed with breast cancer and who were scheduled for at least four chemotherapy treatments. The participants did not receive any homoeopathic remedies to assist with the side effects following the first chemotherapy treatment. The results from the first chemotherapy treatment were utilized to establish each individual’s control results against which, future results would be compared. Participants received their homoeopathic similimum remedies to assist with their second, third and fourth chemotherapies. The appropriate homoeopathic remedy was determined using each patient’s distinguishing, mental, emotional and physical symptoms following each chemotherapy treatment. Each participant completed the Researcher’s Questionnaires (Appendix B) following their chemotherapy treatments and recorded the severity of their nausea, fatigue, vomiting and general symptoms experienced after each of the four chemotherapies. These were handed to the researcher at each follow-up consultation. These results, together with the holistic progress as noted by the researcher at every consultation, were used to determine the efficacy of homoeopathy on the side effects of chemotherapy treatment. This study aimed to reduce the severity and duration of side effects resulting from chemotherapy treatment using individual homoeopathic remedies prescribed. The severity of side effects was graded and monitored for each patient following each chemotherapy session. Of the ten participants involved in this study, eight participants completed all their scheduled chemotherapy sessions. Two of the participants completed only three chemotherapies as their conditions had improved drastically and were not compelled to complete their remaining chemotherapies. Compliance with the homoeopathic treatments was thus effectively 100%. The results of this study indicated that all of the participants reported a statistically significant decrease in side effects after taking the similimum homoeopathic remedies and they also experienced a shorter duration of side effects. All patients in this study were better able to cope with the side effects of chemotherapy whilst taking the similimum Homoeopathic remedies. / Dr. N. Wolf Dr. C.A. Benn Dr. K. Peck

No description available.

No description available.

The mammary gland consists of an organized network of epithelial ducts and lobules. This histoarchitecture can be recapitulated in vitro by culturing mammary epithelial cells as 3D spheroids embedded in a reconstituted basement membrane. I first used this assay to characterize the role of cell-cell and cell-ECM adhesion in the formation and polarization of the apical junction complexes in normal mammary epithelial cells. Cell-cell adhesion alone was sufficient to initiate polarized junction assembly. However, the addition of exogenous ECM generated a spatial polarity signal dependent on laminin-1 and α6 and β1 integrins. This caused clusters of mammary epithelial cells to re-localize the junctional complexes to the center of the spheroid prior to lumen formation. In ductal breast carcinoma, a critical hallmark is the loss of normal polarized tissue architecture without the induction of an epithelial-to-mesenchymal transformation (EMT). Thus, misregulation of molecules that function as polarity determinants may contribute to ductal tumor progression. Podocalyxin is an anti-adhesive glycoprotein that may be involved, as it is important in epithelial morphogenesis, and its overexpression in clinical breast tumors is associated with poor outcome. Despite this, overexpression of podocalyxin in normal mammary epithelial cells did not disrupt 3D morphogenesis or apicobasal polarity. However, its overexpression in non-metastatic breast tumor cells did perturb the architecture and growth of tumor spheroids in vitro and it facilitated subcutaneous tumor growth in vivo without causing an EMT. Mechanistically, podocalyxin localized to and expanded non-adhesive membrane domains and induced microvillus formation that was dependent on its extracellular domain and Rho GTPase-regulated actin polymerization. Podocalyxin also recruited its intracellular binding partners NHERF-1 and ezrin via its cytoplasmic tail. Strikingly, the formation of this protein complex was not required for microvillus formation. Additionally, podocalyxin delayed cell-cell aggregation and decreased the initial adhesion, spreading and strength of attachment of tumor cells to fibronectin where it restricted β1 integrin localization to the basal/attached domain. These alterations in adhesion possibly contributed to podocalyxin's ability to increase growth factor-dependent tumor cell migration. Altogether, these data indicate that podocalyxin overexpression may facilitate a ductal tumor-like progression that involves EMT-independent alterations in tissue architecture. / Medicine, Faculty of / Graduate

Breast cancer is the most commonly diagnosed cancer amongst Canadian women. Though numerous treatments are available, in many instances tumours become refractory or recur. Therefore, understanding the biological events that lead to the progression and therapeutic resistance of breast cancer is essential for the development of novel treatment options for this disease. Numerous members of the protein arginine methyltransferase (PRMT) family, which are the enzymes responsible for catalyzing methylation on arginine residues are aberrantly regulated in breast cancer. Hence, understanding the precise contribution of PRMTs to the development and progression of breast cancer is important. This Thesis will present my findings on the alternatively spliced PRMT1 isoform, PRMT1v2, previously identified to be overexpressed in breast cancer cell lines and here shown to promote breast cancer cell survival and invasion. Second, a novel role is ascribed to PRMT6, another PRMT aberrantly expressed in breast cancer. PRMT6 promotes chemoresistance to the drug bortezomib by mediating stress granule formation through down-regulation of eIF4E. Increased stress granule formation in bortezomib-resistant cancer cells promotes cell survival. Third, DDX3, a prototypical PRMT substrate which is overexpressed in breast cancer cell lines and stimulates transformation of mammary epithelial cells is a novel substrate of PRMT1, CARM1, and PRMT6. Lastly, TDRD3, a reader/effector of arginine methylation also overexpressed in breast tumours regulates breast cancer cell proliferation, anchorage-independent growth and cell motility and invasion.

One modality to improve quality of life, in Breast Cancer Survivors (BCS), is physical activity (PA). Less than 30% of BCS participate in PA. The purpose of this study is to explore BCS’s intention to exercise. Seventy-five BCS patients, undergoing treatment, completed a survey. The survey assessed the following: Health care practitioner influence, Demographics, Stages of Change (SOC), anxiety and depression, perceived barriers to exercise, past and current exercise, and the constructs of the Theory of Planned Behavior (TPB). BCS who were older, had less education, did not exercise before diagnosis, were in the pre-contemplation and contemplation stages, and/or exhibited a low Perceived Behavioral Control had a lower intention to exercise. Incorporating the findings from this research into an intervention may assist with increasing intention to exercise among BCS. / Includes bibliography. / Thesis (MS)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

Background Breast cancer is the most commonly diagnosed cancer in women worldwide. The identification of breast cancer molecular biomarkers would provide a more accurate assessment of individual disease risks and prognosis. Exosomes, small extracellular vesicles, have been shown to contribute to various aspects of cancer development and progression. Within the last decade, the content of exosomes has been increasingly explored as a new source of potential biomarker molecules for early disease detection. Methods Exosomal proteomes of MDA-MB-231, a metastatic breast cancer cell line, and MCF-10A, a non-cancerous epithelial breast cell line, were compared. Proteomic analysis was conducted using nano-liquid chromatography coupled to tandem mass spectrometry. The expression of proteins in MDA-MB-231cells was analyzed using label-free protein quantification methods. For the selection of potential biomarkers, the following criteria were used: (i) proteins must be unique to MDA-MB-231 cells when compared to MCF-10A cells, ii) localized on the membrane, (iii) abundant in breast cancer and (iii) are reported to increase in expression as the disease progresses. The presence of selected proteins on exosomes was verified using flow cytometry methods. Results In total, 1,107 exosomal proteins were identified in both cell lines, 726 of which were unique to the MDA-MB-231 breast cancer cell line. The biomarker selection process identified three exosomal proteins (glucose transporter 1, glypican 1, and “disintegrin and metalloproteinase domain-containing protein 10”) as potential breast cancer biomarkers. The presence of these three proteins was validated using flow cytometry methods. The proteomics dataset was also rich in other interesting breast cancer proteins, such as 16 metastasis-associated proteins and two kinases. Conclusion We demonstrate that breast cancer exosomes are a rich source of protein biomarkers that may be beneficial for diagnosis and prognosis.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a negative sequela of breast cancer treatment that affects approximately one in five patients treated for breast cancer. The median time of BCRL development is three years post breast cancer treatment. The purpose of this study was to compare the incidence of specific factors between two patient populations: patients who developed BCRL within the median BCRL-onset time and patients who developed late onset BCRL (defined as after three years post breast cancer surgery). METHODS: Two cohorts, one with patients who developed BCRL within the median onset time and another with patients who developed late onset lymphedema, were examined. An in-depth chart review was conducted to identify specific factors including age, body mass index, history of cellulitis, cording, seroma, hematoma, and trauma as well as the specific breast cancer treatment each patient received. RESULTS: The results indicated that there was a higher incidence of trauma, cellulitis, and cording in the late onset BCRL group. Additionally, more patients in the late onset group received BCRL-related physical therapy prior to their BCRL diagnosis than patients in the median onset time group. CONCLUSION: Patients with late onset lymphedema had a higher incidence of trauma, cellulitis, and/or cording compared to patients who developed BCRL within three years of surgery. Given that purpose of this study was solely to examine incidence and not significance, further studies must be conducted in order to determine if these are in fact significant risk factors for late onset BCRL. / 2022-06-04T00:00:00Z

Introduction: Breast cancer is the most frequently diagnosed cancer and leading cause of cancer death among women and represents a considerable public health burden in South Africa and other low-middle income countries. Breast cancer management comprises single or combination treatment including surgery, radiotherapy and chemotherapy. Short and long-term complications of these treatments include shoulder morbidities such as pain, decreased range of motion, tightness, weakness, pain, numbness and lymphoedema, and may be present for up to 6 years post-surgery. An understanding of baseline demographic and clinical risk factors can guide rehabilitation and management strategies for high risk patients. Materials and Methods: This study was a cross-sectional analysis of the prevalence of shoulder pain and dysfunction in women attending their post-treatment annual follow up visit for unilateral breast carcinoma. The aim of this study was to quantify the burden of shoulder pain and disability in a tertiary academic hospital in Cape Town, South Africa, and identify potential risk factors for the development of shoulder morbidity. The primary objective of this study was to determine the prevalence of shoulder morbidity and the secondary objective was to evaluate associations between shoulder morbidity and risk factors such as treatment protocol or baseline demographics. Results: The majority of patients were of mixed ancestry, had their left side affected, received ALND and had undergone Modified Radical Mastectomy. The mean age was 60 years with a mean follow-up since surgery of 6 years. Three-quarters of patients reported a presence of pain or disability; 9% experienced severe pain and disability. Multivariable ordinal logistic regression analysis identified race, side, axillary surgery, chemotherapy and age as significant predictors of pain, and chemotherapy a significant predictor of disability. Discussion: The substantial burden of shoulder morbidity in this population represents a significant public health burden. The use of identified clinical and demographic characteristics may guide in the development of survivorship programmes incorporating surveillance and management of these high risk patients.