Recently the traditional primary method of treatment for breast carcinoma — the Halsted radical mastectomy — has been challenged. It is felt by some people that other methods may be more appropriate for certain women. Quality of life and the patient's preferences are being considered in addition to the strictly medical aspects of the problem. One procedure that attempts to increase the quality of life for certain women is the selective biopsy. Women who are proven to have lymph node metastases at the biopsy are spared a mastectomy and treated by radiation since surgery cannot remove all of the cancer. A study was undertaken at the British Columbia Cancer Institute of selective biopsy patients diagnosed between 1955 and 1963 in order to assess the procedure in British Columbia. After studying survival for selective biopsy patients and others, it was concluded that the procedure should continue to be recommended. Since only 14% of the patients now referred to BCCI have had a selective biopsy, I decided to try to find a statistical method for assessing the probability of nodal metastases. The problem is one of statistical classification. The literature on the theory of several statistical models was reviewed. Two models were chosen for the problem: linear discriminant analysis and logistic regression. The classification procedure most often used is discriminant analysis. However, the linear discriminant model assumes a normal distribution and common covariance matrix for the vector of observations. Medical data is often non-normal and even discrete. The logistic probability model works well with such data. Both models were then used to study the selective biopsy problem. The patients of the BCCI study were used as a training set to estimate the parameters of the discriminant function and the logistic probability function. Then each estimated function was used to classify the patients as a measure of the goodness of fit of the models. The logistic regression correctly classified slightly more of the patients than the discriminant analysis did. Because of the iterative nature of the logistic regression, the execution time for the logistic regression was longer than for discriminant analysis, but not beyond practical limits. .The variables that were significant in the statistical analyses could be used to help the physician make a clinical assessment of the lymph nodes of a woman with breast carcinoma. The variables indicate areas where further research would be useful. / Science, Faculty of / Mathematics, Department of / Graduate

Second only to lung cancer, breast is the leading type of cancer among women in the US. Despite all the medical advances over the past few decades, toxicity and increased resistance to standard drug therapy still remains a significant problem. The heterogeneic nature of all cancers has led to a shift in treatment approaches, in that more research is being carried out with combination treatments in the hope that a multidirectional targeting of cancer will be far more effective than the current single treatment options. Our goal was to gain a better understanding of the molecular mechanisms of a nonhydrolyzable ether analog of RRR-[alpha]-tocopherol, 2, 5, 7, 8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (abbreviated [alpha] -TEA), and to investigate its efficacy when used in combination with known chemotherapeutics 9-nitro-camptothecin (9NC), and Paclitaxel (Taxol). The data presented here looks encouraging as it shows a clinically relevant delivery method using [alpha]-TEA and 9NC has the unique ability to reduce primary tumor burden as well as macro and micrometastatic lung and lymph node lesions in an aggressive syngeneic mouse mammary model, while displaying no obvious toxic side effects. The effect of combination treatments on tumor volume appears in part to be moderated by an increase in tumor cell apoptosis and a decrease in tumor cellular proliferation. Next, the intricate molecular mechanism of how [alpha]-TEA alone and in combination with 9NC is able to induce apoptosis in 66cl-4-GFP murine mammary cancer was investigated. The data suggest that the signaling pathway that ultimately leads to apoptosis is caspase dependent, is able to upregulate pro-death players while at the same time downregulate pro-survival proteins such as c-Flip and survivin. Finally, we investigated the efficacy of [alpha]-TEA used in an allograft mouse model following treatment with Taxol. Combination treatments were able to significantly reduce primary tumor burden, decrease lung and lymph node micrometastases, tumor cell proliferation, tumor blood vessel density as well as increase tumor cell apoptosis. Based on the results presented, we propose that [alpha]-TEA when used alone and in combination is an effective, non-toxic option for cancer treatment which warrants further investigation. / text

There is no abstract available for this dissertation. / Department of Educational Studies

Breast cancer is a complex heterogenous disease that consists of several different subtypes displaying distinct behaviors and responses to different treatments. It is the second leading cause of cancer death among women, and is the most commonly diagnosed cancer in women. Although recent developments have helped shed light into this disease, there is still much to investigate. One particular subtype of breast cancer, known as triple-negative breast cancer, remains the most aggressive, as this tumor type is of high histological grade and preferentially affects women with BRCA1 mutations and women who are younger than 40 years of age. Unlike other subtypes with better prognoses, triple-negative breast cancer still has no targeted therapy, and chemotherapy remains the primary systemic treatment. Recently, there has been an increase of interest in the SOXC family of high mobility group transcription factors and their roles in tumor development. Studies have revealed some of the effects that SOXC genes may have on various tumor types. However, further studies are still needed to elucidate the roles, functions, regulations, and mechanisms of these transcription factors. This study aims to focus on one particular gene in the SOXC family known as sex determining region Y-box 11. Recent studies have shown that sex determining region Y-box 11, also known as SOX11, is one of the factors required for maintaining the basal-like breast cancer phenotype and is also critical in regulating growth, migration, invasion, and expression of signature basal-like breast cancer genes. Emerging evidence also reveals that this transcription factor may have an impact on homologous recombination repair when DNA damage occurs, in triple-negative breast cancer. Using SOX11 overexpression and knockout cell models combined with basic science laboratory techniques and omics, the next generation of laboratory tools, this study seeks to explore the role and function of SOX11 in DNA damage in triple-negative breast cancer. The results of this study have confirmed the recent findings of the role of SOX11 in cell proliferation and growth in triple-negative breast cancer. It has also revealed that overexpression of SOX11 in triple-negative breast cancer cell lines leads to an increase in DNA damage, loss of BRCA1 function, and dysregulation in the cell cycle. High expression of SOX11 is also associated with worse prognostic outcomes in triple-negative breast cancer patients. Because overexpression of SOX11 resulted in a loss of BRCA1 function, there may be a potential role for SOX11 in inducing the BRCAness phenotype commonly seen in basal-like breast cancers. The results of this study strongly suggest that SOX11 is involved in defective DNA damage repair pathways. Further studies need to be conducted in order to evaluate SOX11 as an inducer of the BRCAness phenotype, which occurs when there is a homologous recombination repair defect and no germline BRCA1 mutation present. Because of this, SOX11 may also have the potential to act as a functional biomarker for therapies targeting DNA damage, as recent developments in identifying therapies that could potentially target homologous recombination repair defects have been promising.

Inflammatory Breast Cancer (IBC) is a rare, lethal, and understudied form of breast cancer. Although affecting 1-2% of the population, the remission rate is half that of the spectrum of other breast cancers, and most cases present in the advanced stages due to rapid undetectable development. Of the diagnosed cases, systemic chemotherapeutics are relatively ineffective in comparison to non-IBC breast cancer cases, indicating other unique mechanisms driving IBC progression. Historically, the specific sensitivities of a particular tumor type or subtype have been linked to genetic alterations that represent addiction hubs, such as hyperactivation of oncogenes due to mutation. Although some efforts have been made to characterize the molecular fingerprint of inflammatory breast cancers (IBCs), unfortunately, no clinical application has emerged from these studies. Thus, we decided to utilize a different strategy to identify the Achilles' heel of IBC cells. Using shRNA libraries, we performed an unbiased genome-wide loss-of-function screen comparing the gene functions required for survival of IBC and non-IBC cells. Histone deacetylase 6 (HDAC6) emerged as one of the top genes required for IBC cell survival and was further validated. HDAC6 is vital in the cell's unfolded protein response (UPR) to clear misfolded or toxic protein, and IBC cells proved to be preferentially sensitive to this aspect of HDAC6 inhibition, displaying increased protein accumulation, ER stress indicators, and subsequent apoptosis upon failure to clear or refold accumulated proteins. These data indicate HDAC6 is a crucial gene required for IBC cell line survival, in part due to its function in IBC cell UPR. Furthermore, emerging orally bioavailable agents for HDAC6 inhibition make it a promising candidate towards tailored therapeutic implementation in IBC patient trials.

The number of women living with a breast cancer diagnosis will continue to increase with growing breast cancer incidence rates, greater utilization of early detection, and longer length of survival times. The prevalence of complementary and alternative medicine (CAM) is likely to increase as well, making it important to determine the nature and extent of CAM use in this population. This study explored CAM use and the influence of the control constructs in the context of the theory of cognitive adaptation. Computer-assisted telephone interviews were completed with 551 women diagnosed with breast cancer in Portland, Oregon. Results indicated that two-thirds (66%) of the women used at least one CAM therapy during the past 12 months. The majority of women had high perceptions of cancer control and believed the CAM therapies were important in influencing the course of the cancer. Logistical regression analysis found that significant demographic predictors of CAM use were younger age, higher education, and private insurance. Confirmatory factor analysis was used to refine and test the construct validation of the Cancer Locus of Control scale. Results supported a three-factor model (control over cause of cancer, control over course of cancer, and religious control of cancer) of the scale. Results of multinomial logistical regression indicated that higher perceptions of control over the course of the cancer significantly predicted CAM use in three categories. Religious control over the cancer was not a predictor of CAM use. The findings from this study will help health care professionals and policy makers identify patient needs that go beyond surgery, chemotherapy and radiation, and address patient-centered health-related goals and outcomes for optimal health and recovery from breast cancer. / Graduation date: 2002

Not available / text

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences

No description available.

Thesis (Ph.D.)--Indiana University, 2008. / Title from screen (viewed on June 1, 2009). School of Nursing, Indiana University-Purdue University Indianapolis (IUPUI). ADVISOR(S): Janet S. Carpenter. Includes vita. Includes bibliographical references (leaves 227-243).