Differentiation-inducing quinolines as experimental breast cancer agents in the MCF-7 human breast cancer cell model.

The purpose of this work is to develop agents for cancer differentiation therapy. We showed that five antiproliferative quinoline compounds in the National Cancer Institute database stimulated cell differentiation at growth inhibitory concentrations (3-14 microM) in MCF-7 human breast tumor cells in vitro. The differentiation-inducing quinolines caused lipid droplet accumulation, a phenotypic marker of differentiation, loss of Ki67 antigen expression, a cell cycle marker indicative of exit into G0, and reduced protein levels of the G1--S transcription factor, E2F1. The antimalarial quinolines, chloroquine, hydroxychloroquine and quinidine had similar effects in MCF-7 cells, but were 3-10 times less potent than the NSC compounds. NSC3852 and NSC86371 inhibited histone deacetylase (HDAC) activity in vitro and caused DNA damage and apoptosis in MCF-7 cells, consistent with their differentiation and antiproliferative activities. However, the HDAC assay results showed that for other compounds, direct HDAC enzyme inhibition was not required for differentiation activity. E2F1 protein was suppressed by all differentiation quinolines, but not by non-differentiating analogs, quinoline and primaquine. At equivalent antiproliferative concentrations, NSC69603 caused the greatest decrease in E2F1 protein (90%) followed by antimalarials quinidine and hydroxychloroquine. NSC69603 did not cause DNA damage. The other NSC compounds caused DNA damage and apoptosis and reduced E2F1 levels. The physicochemical properties of NSC3852, NSC69603, NSC86371, and NSC305819 predicted they are drug candidates suitable for development as experimental breast tumor cell differentiation agents. We conclude DNA damage and reductions in E2F1 protein are mechanistically important to the differentiation and antiproliferative activities of these quinoline drug candidates.

Patterns of care with regard to surgical choice and application of adjuvant radiation therapy for preinvasive and early stage breast cancer in rural Appalachia.

BACKGROUND: Many disparities exist in treatment of early stage breast cancer. Our objective was to conduct a cross-sectional registry analysis of women with early stage breast cancer in Appalachian Kentucky to identify factors affecting surgical choice [breast conserving surgery (BCS) vs mastectomy] and appropriate use of adjuvant radiation therapy (RT). METHODS: Database collection was done through the Kentucky Cancer Registry. Inclusion criteria included female breast cancer patients diagnosed between 1998 and 2007. Patients were diagnosed with ductal carcinoma in situ or American Joint Committee on Cancer stage I or II disease. Database search was limited to Appalachian residents. Statistical analyses were carried out to identify variables affecting surgical choice, receipt of RT, and survival. RESULTS: Analysis evaluated 5,541 Appalachian patients. The distribution of surgery favored BCS (54.1%) over mastectomy (45.9%). On multivariate analysis, the most significant factors for mastectomy were advanced stage [odds ratio (OR) 2.571, P<0.0001], rural location (OR 2.075, P<0.0001), and insurance status (OR 1.546, P<0.0001). Of patients choosing BCS, 56.2% received adjuvant RT. On multivariate analysis age >70 years (OR 2.506, P<0.0001), rural location (OR 2.416, P<0.0001), and lack of insurance (OR 1.651, P=0.0168) were the strongest predictors for not receiving adjuvant RT. CONCLUSIONS: Mastectomy rate remains higher and the rate of RT after BCS is lower in Appalachian women compared with other contemporary studies of women with ductal carcinoma in situ and early stage breast cancer.

Contralateral prophylactic mastectomy: clinical and pathological features from a prospective database.

INTRODUCTION: In keeping with recently documented national trends, a significant and increasing number of patients will have chosen contralateral prophylactic mastectomy (CPM) based on personal preference, without traditional clinical or pathological indication. METHODS: Women who underwent CPM at the University of Louisville from 2003 to 2009 were selected for this study. Descriptive factors were evaluated such as age, race, family history of breast cancer, laterality, hormone receptor status, stage, grade and histology of the index breast lesion. Statistical analysis was used to compute predictive factors for occult contralateral pathology. RESULTS: A total of 107 patients underwent CPM and had adequate medical information to be included in this study. The median age was 48 years, with 88% being white and 12% being African American. Seventy-six percent of the index breast cancers were infiltrating ductal carcinoma and 12% were infiltrating lobular carcinoma. Five "significant" occult pathologies were found in the prophylactically removed breast. Two of the lesions were ductal carcinoma in situ, 2 were lobular carcinoma in situ and 1 was an invasive mucinous carcinoma. On bivariate analysis, there were no factors identified predictive for occult contralateral pathology. CONCLUSIONS: In line with previously reported data, we noted that fewer than 5% of patients who underwent CPM had pathology in the contralateral breast. We were unable to correlate any clinical or pathological characteristics in women who presented with contralateral breast cancer. This study raises serious questions regarding the clinical utility of CPM in detecting synchronous clinically and radiographically occult contralateral primaries.