Citations

Abstract The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell–dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24−/loCD44+ phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse. [Cancer Res 2009;69(7):2887–95]

Purpose An accurate estimate of a woman's breast cancer risk is essential for optimal patient counseling and management. Women with biopsy-confirmed atypical hyperplasia of the breast (atypia) are at high risk for breast cancer. The Gail model is widely used in these women, but has not been validated in them. Patients and Methods Women with atypia were identified from the Mayo Benign Breast Disease (BBD) cohort (1967 to 1991). Their risk factors for breast cancer were obtained, and the Gail model was used to predict 5-year–and follow-up–specific risks for each woman. The predicted and observed numbers of breast cancers were compared, and the concordance between individual risk levels and outcomes was computed. Results Of the 9,376 women in the BBD cohort, 331 women had atypia (3.5%). At a mean follow-up of 13.7 years, 58 of 331 (17.5%) patients had developed invasive breast cancer, 1.66 times more than the 34.9 predicted by the Gail model (95% CI, 1.29 to 2.15; P < .001). For individual women, the concordance between predicted and observed outcomes was low, with a concordance statistic of 0.50 (95% CI, 0.44 to 0.55). Conclusion The Gail model significantly underestimates the risk of breast cancer in women with atypia. Its ability to discriminate women with atypia into those who did and did not develop breast cancer is limited. Health care professionals should be cautious when using the Gail model to counsel individual patients with atypia.

AbstractRecent studies have shown the importance of helper CD4 T cells in initiating and sustaining tumor-specific CD8 T-cell immunity. This has paved the way for identifying MHC class II epitopes that could be incorporated into class I–based vaccines. In this study, the goal was to identify an HLA-DR–degenerate epitope pool derived from insulin-like growth factor binding protein 2 (IGFBP-2). IGFBP-2, a regulator of insulin-like growth factor action, is overexpressed in the majority of breast and ovarian cancers. Using algorithms, we predicted 29 HLA-DR1–binding epitopes. Binding assays targeting 15 different HLA-DRs revealed that 10 epitopes were degenerate, binding to at least four different HLA-DR variants. An IFN-γ enzyme-linked immunosorbent spot assay was used to assess immunity to these 10 epitopes in 48 patients with either breast or ovarian cancer and 18 controls. Elevated T-cell immunity in patients was detected in 4 of the 10 epitopes (IGFBP2.17, IGFBP2.22, IGFBP2.249, and IGFBP2.293). The cumulative T-cell frequency of these four epitopes was elevated in patients relative to controls. All four peptides are naturally processed and presented to CD4 T-cells. The degenerate pool of peptides covers nearly 80% of patients and may be useful for augmenting CD4 T-cell immunity in patients undergoing immunization. [Cancer Res 2008;68(12):4893–901]

Abstract Studies suggest that underglycosylation of the cell membrane mucin MUC1 may be associated with epithelial ovarian cancer. We identified 26 genes involved in glycosylation and examined 93 single nucleotide polymorphisms (SNP) with a minor allele frequency of ≥0.05 in relation to incident ovarian cancer. Cases were ascertained at the Mayo Clinic, Rochester, MN (n = 396) or a 48-county region in North Carolina (Duke University; n = 534). Ovarian cancer–free controls (n = 1,037) were frequency matched to the cases on age, race, and residence. Subjects were interviewed to obtain data on risk factors and a sample of blood for DNA and genotyped using the Illumina GoldenGate assay. We excluded subjects and individual SNPs with genotype call rates of &lt;90%. Data were analyzed using logistic regression, with adjustment for age and residence. We fitted dominant, log additive, and recessive genetic models. Among Caucasians, nine SNPs in eight genes were associated with risk at P &lt; 0.05 under at least one genetic model before adjusting for multiple testing. A SNP in GALNT1 (rs17647532) was the only one that remained statistically significant after Bonferroni adjustment for multiple testing but was not statistically significant in Hardy-Weinberg equilibrium among controls. Haplotype analyses revealed a global association of GALNT1 with risk (P = 0.038, under a recessive genetic model), which largely reflected a decreased risk of one haplotype (0.10 frequency; odds ratio, 0.07; P = 0.01) compared with the most common haplotype (0.39 frequency). These results suggest that genetic polymorphisms in the glycoslyation process may be novel risk factors for ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(2):397–404)

Abstract Background: Early adolescent weight may affect the risk of postmenopausal breast cancer, and this association may be modified by a family history of breast or ovarian cancer in a first-degree relative, and/or estrogen (ER) and progesterone (PR) receptor status of the disease. Methods: Relative weight at age 12 years (above, below, or average weight compared with peers) and family history were ascertained using a mailed questionnaire in 1986, in the Iowa Women's Health Study, a prospective cohort study of postmenopausal women. Incident breast cancer cases (including ER and PR status) were identified using the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression, and were adjusted for breast cancer risk factors, including body mass index at age 18 years and body mass index at study baseline. Results: Through 2003, 2,503 cases of postmenopausal breast cancer were identified among 35,941 women in the analytic cohort. Compared with women with average weight at age 12 years, there was no association of below average weight with risk of breast cancer (RR, 1.02; 95% CI, 0.92-1.13), whereas women with above average weight had a lower risk (RR, 0.85; 95% CI, 0.74-0.98). There was no evidence of an interaction between weight at age 12 years and family history (P = 0.44). The inverse association of above average weight with risk of breast cancer was strongest for PR− tumors (RR, 0.62; 95% CI, 0.43-0.89), intermediate for ER+ (RR, 0.80; 95% CI, 0.67-0.96) and ER− (RR, 0.77; 95% CI, 0.50-1.19) tumors, and weakest for PR+ tumors (RR, 0.90; 95% CI, 0.74-1.09). These associations were not modified by a family history (all P &gt; 0.18). In a joint ER/PR analyses, the strongest inverse association with above average weight at age 12 years was seen for ER+/PR− (RR, 0.49; 95% CI, 0.29-0.85). Conclusion: Above average weight at age 12 years was inversely associated with risk of postmenopausal breast cancer, and was not modified by a family history of the disease. The inverse association was strongest for ER+/PR− tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(2):374–8)

Quantitation of circulating tumor cells (CTCs) constitutes an emerging tool for the diagnosis and staging of cancer, assessment of response to therapy, and evaluation of residual disease after surgery. Unfortunately, no existing technology has the sensitivity to measure the low numbers of tumor cells (<1 CTC per ml of whole blood) that characterize minimal levels of disease. We present a method, intravital flow cytometry, that noninvasively counts rare CTCs in vivo as they flow through the peripheral vasculature. The method involves i.v. injection of a tumor-specific fluorescent ligand followed by multiphoton fluorescence imaging of superficial blood vessels to quantitate the flowing CTCs. Studies in mice with metastatic tumors demonstrate that CTCs can be quantitated weeks before metastatic disease is detected by other means. Analysis of whole blood samples from cancer patients further establishes that human CTCs can be selectively labeled and quantitated when present at ≈2 CTCs per ml, opening opportunities for earlier assessment of metastatic disease.

Purpose Atypical hyperplasia is a well-recognized risk factor for breast cancer, conveying an approximately four-fold increased risk. Data regarding long-term absolute risk and factors for risk stratification are needed. Patients and Methods Women with atypical hyperplasia in the Mayo Benign Breast Disease Cohort were identified through pathology review. Subsequent breast cancers were identified via medical records and a questionnaire. Relative risks (RRs) were estimated using standardized incidence ratios, comparing the observed number of breast cancers with those expected based on Iowa Surveillance, Epidemiology, and End Results (SEER) data. Age, histologic factors, and family history were evaluated as risk modifiers. Plots of cumulative breast cancer incidence provided estimates of risk over time. Results With mean follow-up of 13.7 years, 66 breast cancers (19.9%) occurred among 331 women with atypia. RR of breast cancer with atypia was 3.88 (95% CI, 3.00 to 4.94). Marked elevations in risk were seen with multifocal atypia (eg, three or more foci with calcifications [RR, 10.35; 95% CI, 6.13 to 16.4]). RR was higher for younger women (< 45; RR, 6.76; 95% CI, 3.24 to 12.4). Risk was similar for atypical ductal and atypical lobular hyperplasia, and family history added no significant risk. Breast cancer risk remained elevated over 20 years, and the cumulative incidence approached 35% at 30 years. Conclusion Among women with atypical hyperplasia, multiple foci of atypia and the presence of histologic calcifications may indicate “very high risk” status (> 50% risk at 20 years). A positive family history does not further increase risk in women with atypia.