Numb protein expression correlates with a basal-like phenotype and cancer stem cell markers in primary breast cancer

Karin Rennstam (1) , Nicole Mcmichael (1) , Pontus Berglund (1) , Gabriella Honeth (1) , Cecilia Hegardt (1, 2) , Lisa Rydén (3) , Lena Luts (4) , Pär-Ola Bendahl (1) , Ingrid Hedenfalk (1)

1 Department of Oncology, Clinical Sciences
2 Lund Stem Cell Center
3 Department of Surgery, Clinical Sciences
4 Department of Clinical Pathology, Clinical Sciences

Decreased expression of Numb, resulting in activation of the proto-oncogene Notch1 and reduction in the tumor suppressor p53, has been demonstrated in mammary carcinomas. The aim of this study was to investigate the relationship between Numb protein expression and clinicopathological characteristics, tumor biological subtypes and putative cancer stem cell markers in a well-characterized cohort of primary human breast cancers. Immunohistochemistry was performed on tissue microarrays of primary invasive breast tumors using a polyclonal anti-Numb primary antibody. Of the 241 tumors evaluated, 50 (21%) displayed deficient or reduced Numb immunoreactivity. Retained Numb expression was significantly correlated to estrogen (ER) and progesterone receptor (PR) positivity ( < 0.001 and  = 0.004, respectively). Interestingly, we found that a higher percentage of the tumors with deficient or reduced Numb expression belonged to the triple-negative (ER-/PR-/HER2−) subgroup compared to tumors with retained Numb expression ( = 0.004). Transcriptional profiling of a subset of these tumors linked and , both downstream targets of Numb, to the triple-negative subgroup in an inverse manner. Typically, subgroups characterized by the low expression of Numb expressed higher levels of and (encoding survivin). We also found deficient expression of Numb in a significantly higher proportion of dependent tumors, which are usually triple-negative, compared to sporadic tumors. The expression of Numb in 14 breast cancer cell lines correlated similarly to their respective molecular subtypes. We further established an inverse correlation between the Numb expression levels and the CD44+/CD24− cancer stem cell phenotype ( = 0.05) in primary tumors. Finally, decreased Numb expression was associated with poorer distant disease-free survival ( = 0.01). Taken together, our results indicate that loss of Numb expression is a marker of tumor aggressiveness, potentially linked to status and a cancer stem cell phenotype in primary breast cancer.

Mots clés: Breast cancer; Basal-like; Numb; Cancer stem cell; CD44/CD24

Karin Rennstam, Nicole Mcmichael, Pontus Berglund, Gabriella Honeth, Cecilia Hegardt, et al.. Numb protein expression correlates with a basal-like phenotype and cancer stem cell markers in primary breast cancer. Breast Cancer Research and Treatment, 2009, 122 (2), pp.315-324. ⟨10.1007/s10549-009-0568-x⟩. ⟨hal-00535402⟩