Basal-like subtype of breast cancer: a review of its unique characteristics and their clinical significance
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- Kobayashi, S. Breast Cancer (2008) 15: 153. doi:10.1007/s12282-008-0034-3
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Subtyping of breast cancers by means of DNA microarray analyses has given rise to the new concept of the basal-like subtype; this subtype is in effect the equivalent of so-called “triple-negative” breast cancer. Basal-like breast cancer has aggressive characteristics, such as high histological grade, mutation of the TP53 gene, and negative hormone receptors. It tends to occur in relatively young women and is highly correlated with suppression of BRCA1 function. The EGFR gene is often overexpressed in this subtype. Here, research carried out in the last few years into the basal-like subtype of breast cancer will be reviewed.
KeywordsBreast cancerBasal-like subtypeTriple negativeBRCA1EGFR
Breast cancer 1
Human epidermal growth factor receptor type2
Epidermal growth factor receptor
Pathological complete response
The range of clinical behaviors and treatment outcomes of breast cancers is dependent not only morphological characteristics, but also biological aspects. The phenotypic diversity of breast cancers has been shown by DNA microarray analyses. The Stanford group provided molecular portraits of breast tumors using a microarray of 1,753 genes . From a scaled-down panel, they identified eight clusters: the endothelial cell gene expression cluster; the stromal/fibroblast cluster; breast basal cell cluster; B-cell cluster; adipose-enriched/normal breast cluster; macrophage cluster; the T-cell cluster; and the breast luminal epithelium cell cluster. In addition, they confirmed the six subtypes of breast cancer: luminal-A, luminal-B, luminal-C, normal breast-like, HER2/neu (HER2) positive and basal-like [2, 3].
A majority of the basal-like subtype does not express the estrogen receptor (ER), progesterone receptor (PgR) or HER2 genes; this is the so-called “triple-negative” type that has poor prognosis . The basal-like subtype has an intimate association with BRCA1 function . Although the strict criterion of subtypes is not yet settled, the basal-like subtype is increasingly important in both fundamental studies and in the clinical management of breast cancer. In this paper, the unique characteristics and clinical behavior of the basal-like subtype is reviewed, with particular emphasis on prognosis and treatment responses.
The origin of naming “basal-like”
DNA expression profiles show that breast cancers can be divided into two major groups, luminal and others . The former group contains three subtypes (A, B and C) that are defined by high expression of ER and related genes. The latter group also contains three subtypes: normal breast-like, which expresses genes included in adipose tissue and nonepithelial cells; the HER2 subtype, which has high specific expression of HER2; and the basal-like subtype that shows high expression of basal/myoepithelial cell-specific genes, including matrix metalloproteinase 14, laminin gamma 2, cytokeratin 17, cytokeratin 5 and integrin beta 4 . Expression of ER and related genes is low to absent in the latter three subtypes [1–4]. The same research group and others have reported further analyses using different sets of genes, including cytokeratin 5 and 17 [1–3, 6, 7]. These analyses showed that the subtypes were distinct with any of these gene sets. The subtypes were well conserved in their responses to primary chemotherapy, with regard to lymph node metastasis, and did not display inter-site variation for large tumors . The alteration of DNA copy numbers was distinctly different between the various subtypes .
Incidence of basal-like subtype
Van’t Veer data
Pre meno. African
Post meno. African
Pre meno. Non-African
Post meno. Non-African
Very nearly, an exceptionally low prevalence (8%) of basal-like subtype in 793 breast cancers from Japanese patients has been reported . Although the distribution of subtypes may vary due to inter-laboratory variance in the scoring of immunohistochemical staining, this extremely low prevalence is not acceptable at all from the aspect of the variance. Together with a high prevalence of luminal A subtype, the authors speculated a close relationship between more favorable biological characteristics and a better prognosis for Japanese breast cancer patients. There is, however, considerable difference in the criterion of negativity for HER2 expression between those reports. Although scores of 0, 1 and 2 for the Hercep test were categorized as negative in many reports [9, 13, 31], only the scores 0 and 1 were categorized as negative in this paper. The reassessment of Japanese cases, therefore, should be done using the same criteria of categorization of HER2 expression.
The subtypes can also be distinguished by examination of in situ carcinomas [12, 20]. Interestingly, however, the incidence of the basal-like subtype is half or less of that of invasive subtypes. In 66 high-grade ductal carcinomas examined in situ, 4 (approximately 6%) were of the basal-like subtype . Given the similarity between reports for the rates of the basal-like subtype in invasive cancers, the comparatively low incidence of this subtype in the in situ cases cannot be explained by differences in methodology and/or inter laboratory variance of analysis. Basal-like in situ carcinomas also show a high nuclear grade and p53 overexpression with an elevated Ki-67 index. Therefore, it would seem that hormone-independent, highly mutated breast cancers can arise at the initial stages of carcinogenesis and appear as invasive cancers with a rapid rate of transformation.
How to identify the subtypes?
Amplified and labeled total RNAs from sample tumors were hybridized using a selected microarray . The dendrogram obtained from the hierarchical clustering of data was analyzed to identify tumor subtypes [1–4, 6, 7, 11]. The analysis of the DNA expression profile is a fundamental and validated procedure for the subtyping of breast cancers with high reproducibility. It is, however, a time-consuming procedure and is technically demanding. An alternative approach, for example the immunohistochemical staining of specifically expressed gene products such as cytokeratin 5/6 and cytokeratin 17, can enable reliable detection of the basal-like subtype of breast cancer [5, 17]. Antibodies for use in staining of P-cadherin, p63 , cytokeratin 8/18 and vimentin  are also available. These antibodies are able to react with their target antigens in tissues that have been subjected to formaldehyde fixation and paraffin embedding. Negative staining of hormone receptors and HER2 can also be informative in determination of cancer subtype.
What are the specific characteristics of the basal-like subtype?
BRCA1-related hereditary breast cancers are relatively rare in Japan. This type of breast cancer is characteristically aggressive with a high histological grade and poor prognosis [23, 24]. It is well known that BRCA1-related hereditary breast cancer is more likely to develop at younger ages. In a study of 32 patients, the 5-year survival rate was 67% compared to 78% in 59,517 nonhereditary breast cancer cases . In contrast, in sporadic cases, patients with a normal BRCA1 protein have a better prognosis than those who lack the protein . The suppression of BRCA1 gene expression, therefore, has a significant influence on the aggressiveness of the cancer.
Since the initial reports on breast cancer subtypes, an intimate correlation has been recognized between cancers with mutation of BRCA1 and classification as basal-like subtype . An analysis of the gene expression profiles of 18 BRCA1 mutated cancers showed that, without exception, they corresponded with that of the basal-like subtype. This high correlation has since been confirmed by other studies using larger patient cohorts [27, 28]. In sporadic breast cancers, however, somatic mutation of the BRCA1 gene has rarely been identified . This apparent discrepancy between the rate of BRCA1 mutations and the incidence of the basal-like subtype in sporadic breast cancers is puzzling. One possible explanation, that methylation of the BRCA1 promoter induces silencing of gene expression, has been investigated. Unfortunately, the conclusions of these studies are not consistent. Matros et al. reported that the ER-positive high-grade tumors (luminal-C subtype) often had methylation . On the other hand, no statistical difference of methylation has been found between the basal-like subtype and other subtypes . Metaplastic carcinomas are included within the basal-like subtype and have an extremely high BRCA1 methylation rate of 63% (17/27) .
Inhibitor of DNA binding-4 (ID4) is a member of the Id family of proteins (Id1-Id4) and functions as a dominant-negative regulator of basic helix-loop-helix transcription factors . The important role of ID4 in regulation of BRCA1 function has been reported on many occasions [33, 34]. A significantly higher expression of ID4 was observed in the basal-like subtype comparing to the control cases . The lower expression of X inactive specific transcript (XIST), a surrogate marker of BRCA suppression, was also observed in the basal-like subtype . The functional abnormality of the p53 gene accelerates BRCA1 gene instability .
In summary, formation of a basal-like phenotype may result not only through DNA mutation or promoter silencing, but also through loss or suppression of BRCA1 function by other means. More information on this topic can be obtained from a recent review of BRCA1 function and the basal-like subtype of breast cancer .
What is the clinical significance of the basal-like subtype?
The prognosis of the basal-like subtype, and of the HER2 expressing subtype, is poor [2–4, 18]. This is a consequence of adverse clinicopathological characteristics, such as mutation of the TP53 gene , high histological grade [5, 6, 9], high Ki-67 score  and negative expression of ER and PgR. The age distribution of the basal-like subtype tends on average to be younger than for other subtypes of breast cancer [5, 10]. Premenopausal patients, therefore, are more often observed in this than other subtypes .
Since a majority of these tumors have the so-called triple-negative characteristics, they do not respond to the therapeutic improvements achieved for hormone-dependent and/or HER2-positive tumors. Therefore, the only treatment option available is that of cytotoxic chemotherapy. In a recent study, 80 patients with primary breast cancer were sub-typed using DNA microarray analysis of a core needle biopsy specimen. The patients were then given primary chemotherapy involving 12 weeks of paclitaxel followed by 5-fluorouracil, doxorubicin, and four courses of cyclophosphamide . The pathological complete response (pCR) rates were extremely high in the basal-like (45%) and HER2 positive subtypes (45%) compared to those in the luminal A/B (7%) and normal breast-like subtypes (0%). This high pCR rate to primary chemotherapy is an encouraging step in the right direction. The good prognosis of patients that had tumors showing pathologic complete response to chemotherapy has been also reported . The improvement of actual survival rate should be validated prospectively.
An overwhelming majority of panelists at the tenth St. Gallen Oncology Conference held in St. Gallen, Switzerland, 14–17 March 2007 highly recommended the use of alkylating agents, such as cyclophosphamide. Although conclusive evidence is not yet available, platinum agents may also be candidates for use in treatment .
Gefitinib is known to be effective in non-small cell lung cancers, which have a high mutation rate of the EGFR gene . The positions of the mutations appear to focus around the active site of the three-dimensional structure of EGFR protein [43, 44]. Interestingly, the mutation is significantly more frequent in Japanese patients compared to American patients (15/58 vs. 1/61), particularly for adenocarcinoma of the lung in young non-smoking Japanese women. Although most EGFR mutations induce hyper-expression of the protein, some suppressive mutations have been found . Gefitinib treatment may be associated with various adverse effects, such as skin rashes, diarrhea, liver injury and interstitial lung disease. These adverse effects of gefitinib, however, are not associated with mutation of the EGFR gene . Ethnic differences in the spectrum of mutations of the EGFR gene in lung cancers have been reported. This suggests that it should be mandatory to perform mutation analyses in the basal-like subtype of breast cancers from Japanese patients.
Human breast cancer cell lines with characteristics of basal-like subtype and/or vimentin-expressing mesenchymal transition type were sensitive to dasatinib, a kind of small molecule kinase inhibitor of src and abl proteins . In vivo studies and clinical investigations, therefore, should be conducted under well-controlled protocols.
Although not yet specified for basal-like subtype breast cancer, antiangiogenetic agents, such as sunitinib, vatalanib and bevacizumab, have considerable potential as a new strategy of choice in breast cancer treatment [47–49].
Molecular subtyping has led to a new era in breast cancer treatment. A majority of so-called “triple-negative” breast cancers are included within the basal-like subtype and have unique characteristics, such as BRCA1 gene dysfunction and overexpression of EGFR and alpha-basic-crystalin, a growth factor inducer . These molecular specificities provide new candidates for treatment targets in the development of new drugs.
The specimen for the cytokeratin staining was kindly provided by Dr. H. Yamashita and T. Toyama, Breast and Endocrine Surgery, Nagoya City University Graduate School of Medical Science.