Breast cancer is a heterogeneous disease, and can be classified according to histological subtypes based on cellular morphology. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most common histological subtypes, accounting for approximately 80% and 12% of cases respectively. ILC exhibits a number of distinct clinico-pathological features in comparison with IDC, and is understudied as a breast cancer subtype. ILC tumours are typically oestrogen receptor positive, HER2 negative, and frequently demonstrate early loss of Ecadherin expression, which is a hallmark of the lobular phenotype. ILC is presently treated in a similar manner to IDC, with treatment generally directed against hormone receptors. Upon acquisition of hormone resistance, limited secondary options are available; patients are rarely candidates for agents targeting HER2, and are recognised to be poorly responsive to chemotherapeutics. We therefore need to advance our understanding of lobular tumour biology, in order to identify suitable biomarkers that will guide the development of targeted therapies for ILC patients. As protein expression levels determine cellular phenotype, a protein-based approach has the potential to provide biologically relevant insight into the mechanisms driving ILC. A range of protein analysis platforms, including reverse phase protein array, label-free mass spectrometry and immunohistochemistry, were therefore used to elucidate biological mechanisms active in the ILC subtype. Such experiments led to the identification of activated PI3K-Akt signalling in mouse and human ILC, suggesting that inhibition of this pathway may be an effective treatment strategy in lobular breast cancer. Preliminary evidence of differences in cytoskeletal and extracellular matrix (ECM) proteins was also acquired, providing an interesting basis for future research. A further major strand of this project was the development of in vitro and in vivo tools, to facilitate further interrogation of lobular biology. This included determination of a representative mouse model of ILC, and generation of primary cancer cells and cancer-associated fibroblasts (CAFs) from patient-derived material. Analysis of CAFS showed differential expression of ECM-associated genes, consistent with proteomic analyses. In addition, a tissue micro-array (TMA) comprising primary ILC and IDC tumours, with associated clinical data, was developed. Immunohistochemical staining of the TMA identified a potential role for IGF-1 pathway signalling in ILC, with increased expression of IGF-1 ligand associating with increased tumour size and metastasis in ILC patients. Taken together, the generation and validation of a range of useful tools in the course of this work has provided useful insight into the unique biology of ILC.

Typescript (photocopy) / 163 leaves, [8] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--Dept. of Surgery, University of Adelaide, 1981

Background: Axillary lymph node dissection as routine part of breast cancer treatment has been questioned in relation to the balance between benefits and morbidity. The purpose of this study is to determine the association of tumor size, age and histological grade with axillary lymph node metastasis, to determine if some patients could be exempted from axillary dissection. Methods: The data are derived from BreastScreen NSW, the government sponsored population-based breast screening program. In New South Wales (NSW) Australia between 1995 and 2002, 7,221 patients with invasive breast carcinoma were diagnosed and 5,290 patients were eligible for this study. The relationship between incidence of positive axillary lymph nodes and three study factors (tumor size, age and histological grade) was investigated by univariate and multivariate analysis. Logistic regression models were used to predict probability of axillary metastases. Results: The incidence of axillary lymph node metastases was 28.6% (95% CI: 27.4%- 29.8%). Univariate analysis showed that age, tumor size and histological grade were significant predictors of axillary lymph node metastases (p<0.0001). Multivariate analysis identified age, tumor size and histological grade remained as independent predictors (p<0.0001). From multivariate analysis, patients with T1a (Less than or equal to 5mm) and grade I tumors regardless of age had 5.2% (95% CI: 1.2%- 9.3%) frequency of node metastases. Patients 70 years or older with grade I, T1a and T1b (6-10mm) tumors had 4.9% (95% CI: 3.2%- 7.5%) and 6.6% (95% CI: 5.3%-8.3%) predicted frequency of node metastases. Conclusions: Tumor size, age and histological grade are predictors of axillary lymph node metastases. Routine axillary lymph node dissection could be avoided in some patient groups with a low frequency of involved lymph nodes if the benefits are considered to exceed the risks.

"October 2003" / Bibliography: leaves 223-271. / xiii, 271 leaves : ill. (some col.), plates (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / 1. Hormonal control of human breast cancer -- 2. General materials and methods -- 3. Proliferative effects of androgens -- 4. Cross-talk between androgen and estrogen signalling pathways -- 5. Androgen receptor function in the MDA-MB-453 cell line -- 6. Gene expression profiles in breast cancer cells: identification of androgen regulated genes -- 7. Regulation of BRCA1 expression -- 8. Regulation of prostate specific antigen expression -- 9. General discussion. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2004

A growing body of work implicates chemokines and their receptors in the progression of various types of cancer, including breast cancer. However, as potent chemotactic factors for leukocytes, chemokines also have the potential to enhance anti-cancer immunity. Evidence suggests that the chemokine CXCL12 and its receptors may be important in a number of aspects of breast cancer progression and site-specific metastasis. Another chemokine, CXCL16, has been identified as a specific chemotactic factor for Type Ipolarised T lymphocytes, which are major effectors of cell-mediated immunity and hence efficacious anti-tumour immune responses. The aim of this study, therefore, was to further elucidate the roles of CXCL12 and CXCL16 in breast cancer development and metastasis. To achieve this, wild-type CXCL12 and CXCL16 and antagonists of CXCL12 and CXCL16 activity, CXCL12[subscript](P2G) and CXCL16[subscript](9-220) respectively, were overexpressed in the 4T1.2 mouse model of breast carcinoma. Overexpression of wild-type CXCL12 potently inhibited both primary tumour growth and metastasis in this model. This was attributed to the induction of an anti-tumour response dependent, in part, on T cells, interferon-g and the cytotoxic mediators perforin and TRAIL. This response was characterised by increased numbers of CD11c⁺ cells in the tumour-draining lymph nodes and enhanced cytolytic activity of lymph node-derived effector cells against tumour cells. Unexpectedly, CXCL12[subscript](P2G) inhibited metastasis of tumour cells to the lungs of tumour-bearing mice, without affecting primary tumour growth. Intravenous injection of tumour cells revealed that CXCL12[subscript](P2G) expression could block metastatic steps occurring post tumour cell escape from the primary tumour, though a role for CXCL12([subscript](P2G) at earlier metastatic steps could not be ruled out. Further work is needed to clarify the precise stages of metastasis at which CXCL12[subscript](P2G) exerts its effects. No obvious effects on primary breast tumour growth were observed when CXCL16 or CXCL16([subscript](9-220) were overexpressed in tumour cells. Interestingly, CXCL16[subscript](9-220) expression inhibited experimental metastasis but not spontaneous metastasis. The findings of this study begin to shed light on the roles of CXCL12 and CXCL16 in breast cancer progression and also highlight the potential therapeutic applications of CXCL12, CXCL16 and/or their antagonists in the treatment of breast cancer and breast cancer metastasis. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297662 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Intrauterine exposures to environmental factors have been hypothesized to influence the risk of breast cancer in adulthood. The majority of epidemiological studies suggest that dietary folate intake is inversely related to breast cancer, however, the evidence have been inconsistent. An animal study was performed to determine the relationship between in utero and postnatal dietary folate intervention and the risk of breast cancer in the DMBA rodent model. Supplementation of maternal and offspring diet with folic acid (5 mg/kg diet) was observed to significantly increase the risk of mammary tumor development in the offspring compared to controls (2 mg/kg diet). Maternal diet and tumor status were also found to be significant predictors of global DNA methylation. Our data suggests that high intrauterine and postnatal exposures to folic acid increases the risk of breast cancer development. Epigenetic modifications may be an underlying mechanism by which folate mediates mammary tumorigenesis in the offspring.

Ecological studies and results from our low-fat, high-carbohydrate dietary intervention trial suggest that different carbohydrates are associated with breast cancer risk in different ways. We examined the association of diet glycemic index (GI), a ranking of carbohydrate containing foods based on their blood glucose raising potential, with breast cancer risk and phenotype. GI was calculated from multiple food records from subjects in our intervention trial using a nested case-control design (220 cases, 440 controls). GI was not associated with risk of total or estrogen receptor positive breast cancer, tumor size or nodal status. GI was strongly positively associated with hormone negative breast cancer. This finding is potentially important as little is known about the etiology of hormone negative breast cancer, which has a worse prognosis than hormone positive breast cancer. However, this finding is based on a small number of cases and should be replicated in a larger sample.

Ecological studies and results from our low-fat, high-carbohydrate dietary intervention trial suggest that different carbohydrates are associated with breast cancer risk in different ways. We examined the association of diet glycemic index (GI), a ranking of carbohydrate containing foods based on their blood glucose raising potential, with breast cancer risk and phenotype. GI was calculated from multiple food records from subjects in our intervention trial using a nested case-control design (220 cases, 440 controls). GI was not associated with risk of total or estrogen receptor positive breast cancer, tumor size or nodal status. GI was strongly positively associated with hormone negative breast cancer. This finding is potentially important as little is known about the etiology of hormone negative breast cancer, which has a worse prognosis than hormone positive breast cancer. However, this finding is based on a small number of cases and should be replicated in a larger sample.

Intrauterine exposures to environmental factors have been hypothesized to influence the risk of breast cancer in adulthood. The majority of epidemiological studies suggest that dietary folate intake is inversely related to breast cancer, however, the evidence have been inconsistent. An animal study was performed to determine the relationship between in utero and postnatal dietary folate intervention and the risk of breast cancer in the DMBA rodent model. Supplementation of maternal and offspring diet with folic acid (5 mg/kg diet) was observed to significantly increase the risk of mammary tumor development in the offspring compared to controls (2 mg/kg diet). Maternal diet and tumor status were also found to be significant predictors of global DNA methylation. Our data suggests that high intrauterine and postnatal exposures to folic acid increases the risk of breast cancer development. Epigenetic modifications may be an underlying mechanism by which folate mediates mammary tumorigenesis in the offspring.

Menopausal symptoms are a concern for peri- and postmenopausal women, and for women who have been treated for breast cancer. Changes in memory are a commonly reported menopausal symptom which can interfere with daily activities, occurring in women who experience natural menopause as well as in women who have an abrupt onset of menopause following treatment for breast cancer. Menopause hormone therapy may be contraindicated or unacceptable for many women, reinforcing the need for well-tolerated, non-hormonal treatments for menopausal symptoms. The purpose of this study was to examine the efficacy of acupuncture to improve the menopausal symptom of memory changes in breast cancer survivors, and was a secondary analysis of a placebo-controlled, randomized clinical trial. The Framework for Interactions between the Individual and the Environment was the conceptual framework that guided the study.&lt;br&gt;Subjects in the parent study were randomized to either the experimental group (symptom-specific acupuncture), control group (non-symptom-specific acupuncture), or enhanced usual care group (instruction on health-related topics). Each group received twelve intervention sessions over an 8-week period. Sixty subjects indicating a positive response to memory items on instruments at baseline were selected for this secondary analysis. The Daily Symptom Diary, Kupperman Index, and Menopause-Specific Quality of Life Questionnaire (MENQOL) measured frequency or severity of perceived memory changes at baseline, midpoint, and end of treatment.&lt;br&gt;Frequency distributions were used to summarize the data. There were no statistically significant results from the Daily Symptom Diary. Improvement in the enhanced usual care group compared to the acupuncture groups was seen on the Kupperman Index, and validity concerns for this instrument were reviewed. Analysis of the MENQOL data revealed more positive change in the acupuncture groups in improvement of memory than in the enhanced usual care group. These findings support the need for further exploration of targeted interventions such as acupuncture to improve memory difficulties for menopausal women and breast cancer survivors, particularly as advances are made in the understanding of the mechanisms of cognitive change. Acupuncture remains promising as a non-hormonal treatment for menopausal symptoms and merits further investigation. / School of Nursing; / Nursing / PhD; / Dissertation;