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. 2010 Jun;176(6):2911-20.
doi: 10.2353/ajpath.2010.091125. Epub 2010 Apr 15.

Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome

Andrey I Khramtsov  1 , Galina F Khramtsova, Maria Tretiakova, Dezheng Huo, Olufunmilayo I Olopade, Kathleen H Goss
Affiliations

Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome

Andrey I Khramtsov et al. Am J Pathol. 2010 Jun.

Abstract

Although Wnt/beta-catenin pathway activation has been implicated in mouse models of breast cancer, there is contradictory evidence regarding its importance in human breast cancer. In this study, invasive and in situ breast cancer tissue microarrays containing luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)(+)/ER(-) and basal-like breast cancers were analyzed for beta-catenin subcellular localization. We demonstrate that nuclear and cytosolic accumulation of beta-catenin, a read-out of Wnt pathway activation, was enriched in basal-like breast cancers. In contrast, membrane-associated beta-catenin was observed in all breast cancer subtypes, and its expression decreased with tumor progression. Moreover, nuclear and cytosolic localization of beta-catenin was associated with other markers of the basal-like phenotype, including nuclear hormone receptor and HER2 negativity, cytokeratin 5/6 and vimentin expression, and stem cell enrichment. Importantly, this subcellular localization of beta-catenin was associated with a poor outcome and is more frequently observed in tumors from black patients. In addition, beta-catenin accumulation was more often observed in basal-like in situ carcinomas than other in situ subtypes, suggesting that activation of this pathway might be an early event in basal-like tumor development. Collectively, these data indicate that Wnt/beta-catenin activation is an important feature of basal-like breast cancers and is predictive of worse overall survival, suggesting that it may be an attractive pharmacological target for this aggressive breast cancer subtype.

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Figures

Figure 1
Figure 1
A shift in β-catenin localization from the membrane to the cytosol and nucleus is associated with breast cancer development. The subcellular localization of β-catenin was analyzed in normal breast (n = 95), DCIS lesions (n = 80), invasive breast cancers (n = 119), and lymph node metastases (n = 52) specimens. A: Membranous β-catenin score was higher in normal breast tissue than in carcinoma in situ, invasive cancer, and lymph node metastases (P < 0.0001). Both cytosolic (B) and nuclear (C) β-catenin score were lower in normal breast tissues than in situ and invasive cancers and metastases (P < 0.0001). In all graphs, the x axis describes the immunohistochemical score, ranging from 0 (no staining) to 3 or 4 (highest intensity and/or percentage of positive cells) as described in the Materials and Methods and Table 2.
Figure 2
Figure 2
Cytosolic and nuclear β-catenin is most frequently observed in basal-like breast cancers. The subcellular localization of β-catenin was analyzed in 66 luminal A, 6 luminal B, 32 basal-like, and 11 HER+/ER− invasive cancers. A–C: While there was no segregation of membrane-associated β-catenin (A) among different subtypes of invasive breast cancer, a higher percentage of basal-like tumors expressed cytosolic (B) or nuclear (C) β-catenin (28/32 and 23/32, respectively) than luminal A (15/66 and 2/66, respectively), luminal B (3/6 and 2/6, respectively), and HER2+/ER− tumors (6/11 and 4/11, respectively). P < 0.05 for all comparisons between basal-like and other tumor types except with HER2+/ER− for cytosolic β-catenin. D: β-catenin immunolocalization (arrowheads) is observed predominantly at the membrane of luminal A, luminal B, and HER2+/ER− tumors. Nuclear and cytosolic β-catenin (arrows) is most prominent in basal-like breast cancers. A sporadic colon carcinoma is shown as a positive control for β-catenin accumulation in the cytosol and nuclei. Scale bars, 50 μm.
Figure 3
Figure 3
Invasive breast cancers with high cytosolic and nuclear β-catenin are associated with poor survival. Kaplan–Meier overall survival curves are presented for 117 patients with invasive breast cancers according to expression of membranous (A), cytosolic (B), and nuclear (C) β-catenin. In contrast to a lack of association of membrane-associated β-catenin with overall survival, high levels of cytosolic (score of 3) or nuclear (score of ≥2) β-catenin expression is predictive of poor outcome (P = 0.0005 and P = 0.039, respectively).
Figure 4
Figure 4
The invasive breast cancers with cytosolic and nuclear β-catenin are enriched in stem cell populations. A: CD44 and CD24 immunohistochemistry was performed to identify a CD44+/CD24− stem cell population in luminal A (n = 65), luminal B (n = 6), HER2+/ER− (n = 11), and basal-like (n = 32) tumors. The percentage of invasive cancers with high CD44+/CD24− scores (>3) is significantly higher in basal-like breast cancers compared with other tumor subtypes (P = 0.0001). B: Immunolocalization of β-catenin and the identification of the CD44+/CD24− profile on serial sections of basal-like breast cancers illustrate that the same tumor cells have cytosolic and nuclear β-catenin (arrows) and are CD44-positive but CD24-negative (arrowheads). In contrast, membrane-associated β-catenin (arrows) colocalizes with CD44-negative/CD24-positive cells (arrowheads) in a luminal A tumor, for example. Scale bars, 50 μm. C: Kaplan–Meier survival curves show that there is no significant difference in overall survival of breast cancer patients when the tumors are stratified by the percentage of CD44+/CD24− tumor cell populations (P = 0.98).
Figure 5
Figure 5
Cytosolic and nuclear β-catenin is observed in basal-like carcinoma in situ lesions. The subcellular localization of β-catenin was analyzed in 54 in situ carcinomas, composed of four molecular subtypes (40 luminal A, 3 luminal B, 5 basal-like, and 6 HER2+/ER−). Like invasive cancers, there was no segregation of membrane-associated β-catenin (A) among different subtypes of carcinoma in situ. However, a higher percentage of basal-like tumors expressed cytosolic (B) and nuclear (C) β-catenin (5/5 for both) than luminal A (7/40 and 0/40, respectively), luminal B (1/3 and 0/3, respectively), and HER2+/ER− lesions (4/6 and 2/6, respectively). P < 0.001.
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