Cancer stem cell markers are enriched in normal tissue adjacent to triple negative breast cancer and inversely correlated with DNA repair deficiency.

INTRODUCTION: We hypothesized that cells present in normal tissue that bear cancer stem cell markers may represent a cancer cell of origin or a microenvironment primed for tumor development, and that their presence may correlate with the clinically defined subtypes of breast cancer that show increased tumorigenicity and stem cell features. methods: Normal tissues sampled at least 5 cm from primary tumors (normal adjacent tissue) were obtained from 61 chemotherapy-naive patients with breast cancer treated with mastectomy. Samples were stained simultaneously with immunofluorescence for CD44/CD49f/CD133/2 stem cell markers. We assessed the association between CD44+CD49f+CD133/2+ staining in normal adjacent tissue and breast cancer receptor subtype (defined by the expression of the estrogen (ER), progesterone (PR), or human epidermal growth factor-2 (Her2) receptors). We also examined the correlation between CD44+CD49f+CD133/2+ immunofluorescence and each of two previously published gene signatures, one derived from stem-cell enriched tissue and one from BRCA mutated tissue expected to have defective DNA repair. RESULTS: Patients with triple negative breast cancer (ER­/PR­/HER2­) expressed CD44+CD49f+CD133/2+ in 9 of 9 normal adjacent tissue samples compared with 7 of 52 ER+ and/or Her2+ tumors (P < 0.001). Further, expression of CD44+CD49f+CD133/2+ by normal adjacent tissue correlated positively with a stem cell-derived tumorigenic signature (P <0.001) and inversely with a defective DNA-repair signature (P <0.001). CONCLUSION: Normal cells bearing cancer stem cell markers are associated with the triple negative receptor subtype of breast cancer. This study suggests stem cell staining and gene expression signatures from normal breast tissues represent novel tissue-based risk biomarkers for triple negative breast cancer. Validation of these results in additional studies of normal tissue from cancer-free women could lay the foundation for future targeted triple negative breast cancer prevention strategies.

A review of body size and breast cancer risk in Hispanic and African American women.

Obesity is an epidemic in the United States, especially among Hispanics and African Americans. Studies of obesity and breast cancer risk have been conducted primarily in non-Hispanic whites. There have been few studies of the association between body mass index (BMI) or weight gain and the risk of breast cancer in minorities, and the results have been inconsistent. Because most studies are conducted primarily in non-Hispanic whites, the etiology of breast cancer in minorities is not well understood. The authors of the current report reviewed the literature on the association between obesity, weight, and weight gain and breast cancer in minorities using a combination of the Medical Subject Heading (MeSH) terms "obesity," "body mass index," "weight," "weight gain," "Hispanic," and "African American." Only publications in English and with both risk estimates and 95% confidence intervals were considered. Forty-five studies of body size and breast cancer risk in non-Hispanic whites were identified. After an exhaustive search of the literature, only 3 studies of body size and breast cancer were conducted in Hispanic women were identified, and only 8 such studies in African American women were identified. The results were inconsistent in both race/ethnicity groups, with studies reporting positive, inverse, and null results. Thus, as obesity rates among Hispanics and African Americans continue to rise, there is an urgent need to identify the roles that both obesity and adult weight gain play in the development of breast cancer in these minorities. Additional studies are needed to provide more understanding of the etiology of this disease and to explain some of the disparities in incidence and mortality.

Effect of lapatinib on the development of estrogen receptor-negative mammary tumors in mice.

Lapatinib, a selective orally available inhibitor of epidermal growth factor receptor (EGFR) and ErbB2 receptor tyrosine kinases, is a promising agent for the treatment of breast cancer. We examined the effect of lapatinib on the development of mammary tumors in MMTV-erbB2 transgenic mice, which express wild-type ErbB2 under the control of the mouse mammary tumor virus promoter and spontaneously develop estrogen receptor (ER)-negative and ErbB2-positive mammary tumors by 14 months of age. Mice were treated from age 3 months to age 15 months with vehicle (n = 17) or lapatinib (30 or 75 mg/kg body weight; n = 16 mice per group) by oral gavage twice daily (6 d/wk). All statistical tests were two-sided. By 328 days after the start of treatment, all 17 (100%) of the vehicle-treated mice vs five (31%) of the 16 mice treated with high-dose lapatinib developed mammary tumors (P < .001). Among MMTV-erbB2 mice treated for 5 months (n = 20 mice per group), those treated with lapatinib had fewer premalignant lesions and noninvasive cancers in their mammary glands than those treated with vehicle (P = .02). Lapatinib also effectively blocked epidermal growth factor-induced signaling through the EGFR and ErbB2 receptors, suppressed cyclin D1 and epiregulin mRNA expression, and stimulated p27 mRNA expression in human mammary epithelial cells and in mammary epithelial cells from mice treated for 5 months with high-dose lapatinib. Thus, cyclin D1, epiregulin, and p27 may represent useful biomarkers of lapatinib response in patients. These data suggest that lapatinib is a promising agent for the prevention of ER-negative breast cancer.