Basal-like breast carcinoma: a phenotypically distinct entity.
Abstract: * Gene microarray profiling of human breast carcinomas has recently categorized invasive breast carcinomas into 5 distinct subtypes; luminal A, luminal B, normal breastlike, human epithelial growth factor receptor 2 (HER2) overexpressing, and basal-like. Basal-like breast carcinomas are characterized by high expression of basal cytokeratins; low or absent expression of estrogen receptor, progesterone receptor, and HER2/neu; and expression of epidermal growth factor receptor (EGFR) and/or c-kit, and they are frequently associated with breast cancer 1 (BRCA1) mutations and poor clinical outcome. Recent studies have begun to provide insights into the molecular genetics, biology, morphology, and clinical outcome of this subtype of breast carcinoma. We reviewed the literature related to basal-like breast carcinomas to better understand this clinically significant subtype of breast carcinoma.

(Arch Pathol Lab Med. 2010;134:130-133)
Article Type: Report
Subject: BRCA mutations (Health aspects)
BRCA mutations (Research)
Breast cancer (Risk factors)
Breast cancer (Genetic aspects)
Breast cancer (Research)
DNA microarrays (Usage)
Growth factor receptors (Physiological aspects)
Growth factor receptors (Research)
Authors: Haupt, Bisong
Ro, Jae Y.
Schwartz, Mary R.
Pub Date: 01/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: Jan, 2010 Source Volume: 134 Source Issue: 1
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230416482
Full Text: Breast cancer is one of the most common human neoplasms, accounting for 22% of all cancers in women worldwide. (1) The incidence rate is higher in North America, Europe, and Australia than in the less developed regions of Africa and Southern and Eastern Asia. Breast cancer is a highly heterogeneous group of cancers, with diversity in its morphology, molecular genetics, biology, and clinical outcome.

Conventionally, invasive human breast carcinomas have been classified morphologically into infiltrating ductal and lobular carcinoma, tubular carcinoma, mucinous carcinoma, medullary carcinoma, invasive papillary carcinoma, metaplastic carcinoma, and a few uncommon types. Recently, gene expression profiling, a method using cDNA microarray to explore gene expression patterns, has classified breast cancer into 5 distinct subtypes based on variations in gene expression patterns. These 5 subtypes are luminal A and luminal B, normal breastlike, human epithelial growth factor receptor 2 (HER2) overexpressing, and basal-like subtypes. (2) Each subtype of tumors expresses a distinct set of genes. Basal-like subtype was characterized by high expression of cytokeratins (CKs) 5 and 17, laminin, and fatty acid-binding protein 7, whereas HER2 overexpressing was characterized by high expression of several genes in the ERBB2 amplicon at 17q22.24, including ERBB2 and GRB7 (Table). In this classification, tumors with the same gene expression pattern are grouped together, which provides a mechanism for studying the association of gene expression profiles with tumor morphology, biologic behavior, response to therapy, and clinical outcome of patients.

Gene expression profiling of tumors has not gained access to the clinical application. Morphology of basal-like breast carcinomas is not unique and overlaps with many other subtypes of breast cancer. Many studies have tried to define basal-like breast carcinoma using immunohistochemical methodology. Different criteria have been used. Some investigators defined basal-like breast carcinomas as expressing at least one of the basal CKs (CK5, CK14, and CK17) (3-7) or a combination of 2 basal CKs (CK5/6 and CK14 or CK17). (8,9) Others have included lack of expression of estrogen receptor (ER) and HER2/neu in addition to expression of basal CKs, most commonly CK5/6, (8) or lack of expression of ER, progesterone receptor (PR), and HER2/neu and expression of one basal CK, epidermal growth factor receptor (EGFR), and/or c-kit. (9) Different criteria used certainly affect the tumor composites defined as basal-like breast carcinomas immunohistochemically, and probably the prognostic significance observed. Precise criteria are now needed to standardize the clinical studies on this group of tumors.

In this paper, we have reviewed tumor cell origin, morphology, immunophenotype, and clinical outcome of basal-like breast carcinomas for us to better understand this group of aggressive breast cancer.

TUMOR CELL ORIGIN

The cell origin of breast carcinoma is unclear and has been studied for decades. The main functional units of the human breast are terminal duct lobular units, which contain 2 types of cells: luminal/glandular and basal/myoepithelial. Luminal cells express CKs 7, 8/18, and 19; ER; and epithelial membrane antigen. Basal/myoepithelial cells express smooth muscle actin, p63, CK5/6, CK17, and CK14. The functional terminal duct lobular units can be generated after transplanting isolated epithelial cells from different regions of mammary glands into the cleared mammary fat pads of mice, which has led to the development of the mammary stem cell hypothesis. (10)

Stem cells are defined as cells with a capacity for both self-renewing to maintain the stem cell compartment and differentiating to generate specialized cells that can form organs and ensure their normal functioning.

Efforts have been made to identify and characterize mammary stem cells. A group of cells called "side population" and another group of cells called label-retaining cells from murine mammary were identified. (11,12) Both side population and label-retaining cells were relatively undifferentiated, but they grew as typical differentiated epithelial clones when they were cultured. Transplantation of murine side population and label-retaining cells at limiting dilution into cleared mammary fat pads generated epithelial ductal and lobular structures. Studies of human mammary stem cells have yielded results similar to those in mice. A distinct population of cells in human adult breast epithelia expressing CK5 was identified. (13) These cells were able to differentiate toward glandular epithelium and myoepithelium through intermediate cells expressing CK5/CK8/CK18/CK19 and CK5/SMA. Another population of cells expressing epithelial-specific antigen was also isolated at the same time from human breast. (14) This cell population was able to regenerate itself, myoepithelial cells, and to form terminal duct lobular units. These studies provide evidence of the presence of mammary stem cells, which have the ability to self-regenerate and differentiate into breast parenchyma. On the other hand, tumorigenic breast cancer cells were recognized (15) from primary or metastatic sites in human patients. As few as 200 cells were able to form tumors following transplantation into NOD/SCID mice (NOD being a strain of mice genetically prone to developing diabetes and SCID indicating severe combined immunodeficiency). Analysis of tumors formed in the mice demonstrated that the tumors were composed of 2 populations of cells: a minor population expressing epithelial-specific antigen and CD44, and a major population of cells expressing CD44 but not epithelial-specific antigen. The population of cells expressing epithelial-specific antigen and CD44 has a capacity to significantly proliferate, differentiate, and form new tumors.

The above investigations clearly provide evidence of the existence of stem/progenitor cells in mammary glands. It is believed that cancer stem cells derive from normal stem cells because of genetic and epigenetic changes. Because adult stem cells are slow-dividing, long-lived cells, these cells are able to accumulate the multiple mutations that may cause a transformation of stem cells. As a result, stem cell self-renewal and differentiation functions are disrupted, which may drive a process of carcinogenesis. Depending on the identity of genomic alterations, generated tumors may exhibit different phenotypes.

MORPHOLOGY

Breast cancers are a heterogeneous group of tumors with respect to morphology, molecular genetics, phenotype, biologic behavior, and their responsiveness to treatment. In general, breast carcinomas have been diagnosed by morphology alone. Some investigators have addressed identifying basal-like breast carcinomas on a purely histomorphologic basis.

In a study (16) conducted on 56 breast carcinomas with known microarray profiles, basal-like tumors were predominantly infiltrating ductal carcinomas, not otherwise specified (21 of 23) and a few metaplastic carcinomas (2 of 23). A few other types, like basaloid carcinoma and adenoid cystic carcinoma, were reported. (17) Most tumors had solid architecture with high histology grade (3 of 3), high mitoses (>25 per 10 high-power fields), frequent geographic necrosis, and no tubule formation. Some tumors showed ribbonlike architecture. A subset of tumors had atypical medullary features, including a pushing or partial pushing border, syncytial arrangement of tumor cells, and a marked stromal lymphocytic infiltrate at the tumor edge. Others with features of metaplastic carcinoma contained components of spindle cells, squamous metaplasia, and matrix production. Most tumor cells had a high nuclear to cytoplasmic ratio, scant cytoplasm, round to oval nuclei, and prominent nucleoli. Nuclear chromatin pattern ranged from coarse to vesicular. Some of the above features are also identified by other studies. (9,18) In addition to the above features, a study (4) demonstrated that basal-like breast carcinomas were associated with the presence of central scar. However, tumors with central acellular scar have been described by other investigators (7,19) as more common in a group tumor expressing myoepithelial markers, such as smooth muscle actin and p63. These tumors are more commonly associated with younger patients and have a morphology similar to basal-like breast carcinoma. In our experience, basal-like breast carcinomas are predominantly infiltrating ductal carcinoma with solid growth pattern and high nuclear and histologic grade. Atypical medullary carcinoma with a pushing border, mild to moderate lymphocytic infiltration, and a syncytial growth pattern can be seen. Tumors with polygonal tumor cells and squamoid features are sometimes present.

Basal-like and luminal tumors are dissimilar in morphology. There is an overlap in the histology of basal-like and HER2-overexpressing subtypes. The features of medullary, BRCA1-related, metaplastic tumors are limited to the basal-like subtype.

Medullary and BRCA1-related tumors are both high-grade tumors with high mitotic activities, a syncytial growth pattern, a prominent pushing margin, and lymphocytic infiltrate. (20,21) It is difficult to distinguish medullary and BRCA1-mutated tumors from basal-like carcinomas because 95% of medullary carcinomas and 88% of BRCA1-related tumors are a subtype of basal-like breast carcinomas with a basal-like gene profile. However, medullary carcinoma has a complete circumscription pushing border, a syncytial growth pattern, and more prominent lymphocytic infiltration, which are not usually seen in basal-like breast carcinoma. Tumors of younger patients with the above morphology suggest the possibility that the patients may carry germline BRCA1 mutations.

Metaplastic breast carcinoma was recognized as a distinct pathologic entity in 2000. Metaplastic breast carcinoma is very uncommon and is a phenotypically very diverse tumor composed of epithelial and mesenchymal components. Five categories of metaplastic breast carcinoma were described,22 including squamous cell carcinoma, spindle cell carcinoma, matrix-producing carcinoma, carcinosarcoma, and metaplastic carcinoma with osteoclastic giant cells. Metaplastic breast carcinoma usually expresses basal CKs. Diagnosis of this tumor frequently requires examining the entire tumor resected with the aid of immunohistochemical staining. Patients with metaplastic breast carcinoma usually have poor clinical outcome.

Whether there is a precursor lesion (basal-like ductal carcinoma in situ) of invasive basal-like breast carcinoma is not known. A small population (6%-8%) of ductal carcinoma in situ sharing an immunophenotype with invasive basal-like breast carcinoma was identified. (23,24) In addition, coexistence of ductal carcinoma in situ and invasive basal-like breast carcinoma also was reported. (18) Most often, the in situ component was only focally present, in no more than 10% of the entire tumor volume, often on the immediate periphery of the tumor, and not associated with any atypical ductal hyperplasia. (18) These findings indicate that basal-like ductal carcinoma in situ could serve as a precursor lesion for invasive basal-like breast carcinoma. A small percentage of in situ component and an absence of atypical ductal hyperplasia could be due to the fact that these tumors grow very rapidly, become invasive, and in most instances obliterate the in situ carcinoma from which they arise.

IMMUNOPHENOTYPE

Cytokeratins are selectively expressed in different types of breast carcinomas. Basal-like breast carcinomas were so named, before the era of gene microarray profiling, because of their expression of basal CKs, such as CK5/6, CK14, and CK17, expressed by basal/myoepithelial cells of the normal breast. However, basal-like breast carcinomas do not express all basal CKs. These tumors may express one or more basal CKs. Most frequently expressed CKs are CK5/6, in up to 70% of basal-like breast carcinomas, (9,16) followed by CK14, in up to 41.2% and, least frequently, CK17. Some basal-like breast carcinomas have myoepithelial differentiation with expression of smooth muscle actin, CD10, or p63. (18) In addition, basal-like breast carcinomas do express luminal CKs, like CK7, CK8/18, and CK19, that are expressed by luminal epithelial cells in normal breast tissue. Positivity of luminal CKs is seen in up to 84% of basal-like carcinomas. (9,16)

In cDNA microarray studies, basal-like breast carcinomas expressed low or no ER and HER2/ neu genes. Immunohistochemically, some authors defined that basal-like breast carcinomas are negative for ER, PR, HER2, (9,24) and the so-called triple-negative phenotype. Human epithelial growth factor receptor 1 (HER1) immunoactivities have been identified in a portion of basal-like breast carcinomas, ranging from 45% (7,9,23) to 75%, (16,24) and only in about 5% of non-basal-like breast carcinomas and an even lower percentage of ER-positive breast cancers. (23) About half of basal-like breast carcinomas have p53 gene mutations with immunoreactivity to p53 protein. (7,9,25) High Ki-67 index was observed in 67% of cases. (25) In addition, basal-like breast carcinomas are positive for P-cadherin (83%) and p63 (55%) and are negative for B-cell lymphoma 2 (63%), whereas luminal subtype tumors are negative for P-cadherin (80%) and p63 (85%) and are positive for B-cell lym phoma 2 (56%). (26)

There is no general consensus on the immunophenotypic criteria of basal-like breast carcinomas, which were defined recently by gene profiling. Standardized criteria may facilitate further study on this group of tumors. If using only basal CKs to define basal-like breast carcinoma, almost half of basal-like breast carcinomas would be missed, and a small fraction of HER2/ neu-expressing tumors would be classified as basal-like breast carcinoma. (9,23) Reliance on the lack of expression for ER, PR, and HER2/ neu would risk misclassification due to technical failures. We use a panel of ER (-), PR (-), HER2/neu (-), 1 basal CK (+), HER1 (+), and/or c-kit (+) to define basal-like breast carcinoma, which has also been proposed by others. (18,23) We include HER1 and c-kit in the panel because HER1 and c-kit are highly expressed in basal-like breast carcinoma and rarely expressed in non-basal-like breast carcinoma; furthermore, the association of HER1 and c-kit expression may have an important application in patients for whom an EGFR-targeted and c-kit-targeted therapy might be a treatment option. Using this panel is compatible with the gene expression profile of basal-like carcinomas, with a sensitivity of 76% and a specificity of 100%. (23) All of these phenotypic markers can be performed immunohistochemically. In addition, basal-like breast carcinomas are associated with a higher rate of BRCA1 and p53 mutations than the other subtypes of breast carcinomas.

CLINICAL OUTCOME

Recently, a great deal of attention has been focused on the relationship between gene microarray profiling and clinical outcome of breast cancer. Sorlie et al (2) studied 49 patients with locally advanced breast cancer without distant metastases. Mean follow-up time was 66 months. All 5 subgroups (defined by gene microarray) were significantly different in overall and relapse-free survival, with the basal-like group associated with the shortest survival. Similar results also were observed by several other investigators. (23,27) Although in the Nielson et al (23) study, the disease-specific survival of patients with basal-like breast carcinomas was shorter than that of patients with ER-positive tumors, whereas the disease-specific survival of patients with HER2-positive tumors was shorter than that of patients with basal-like breast carcinomas, their data were collected before the use of trastuzumab therapy for HER2/ neu-positive tumors.

Several groups (4,6,28) studied the clinical outcome of basal breast carcinomas (defined by expression of basal CKs) and compared these tumors with nonbasal breast carcinomas. Their results showed that the disease-free and overall survival rates of basal breast carcinoma patients were significantly shorter than those of nonbasal breast carcinoma patients. In patients with negative lymph nodes, the expression of basal CKs was a prognostic factor independent of tumor size, grade, HER2/neu, and ER status. (6) However, in patients with positive lymph nodes, the expression of the basal CKs as a prognostic factor was uncertain. (6,29) Another study (30) found that in patients with negative lymph nodes, the prognosis of CK14-positive breast cancer patients was the same as that of CK14-negative breast cancer patients in the first 5 years, but for the long term (more than 5 years), the prognosis of patients with CK14-positive breast cancer was better than that of patients with CK14-negative breast cancer. In patients with positive lymph nodes, however, CK14-positive cases were associated with a poorer prognosis. The authors believe that basal tumors can be divided into "good" and "bad." The bad basal tumors relapse early and have frequent brain metastasis and are associated with poor prognosis. Clinicopathologic parameters cannot discriminate between good and bad basal tumors. However, the pattern of CK14 expression does show the difference in prognosis. Diffuse CK14 staining (more than 90%) seems to fall largely into good basal tumors. This theory needs to be further studied.

In summary, basal-like breast carcinomas have emerged recently as a substantive and distinct group of invasive breast carcinomas. Most studies provided evidence that basal-like breast carcinomas are associated with a worse clinical outcome than that of other subtypes of breast cancer. However, the other studies showed slightly different results. The discrepancy may be due to the lack of standardized criteria in defining the basal-like breast carcinoma. Nevertheless, these tumors have a characteristic morphology and phenotype. With the combination of the characteristics of morphology and immunophenotype, diagnosis of basal-like breast cancer can be made pathologically. Gene microarray profiling provides a mechanism for studying the association of gene expression profiles with biologic behavior and the clinical outcome of this subtype of breast carcinoma. Research on tumor stem cells may guide the search for better therapeutic modalities and provide a basis for developing cancer stem cell-targeted therapy.

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Bisong Haupt, MD; Jae Y. Ro, MD, PhD; Mary R. Schwartz, MD

Accepted for publication March 16, 2009.

From the Department of Pathology (Drs Haupt, Ro, and Schwartz) and Weill Medical College of Cornell University (Drs Haupt and Ro), The Methodist Hospital, Houston, Texas. Dr Haupt is now with the Department of Pathology, Saint Louis University, St Louis, Missouri.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Bisong Haupt, MD, Department of Pathology, Saint Louis University, 1402 S Grand Blvd, St Louis, MO 63104 (e-mail: bisongxu@yahoo.com).
Gene Expression by Different Subtypes of
Breast Carcinoma

Subtype              Genes Expressed

Basal-like           Keratins 5 and 17, laminin, fatty
                       acid-binding protein 7, absent ER
HER2 overexpress     ERBB2 and GRB7, low to absent ER
Normal breastlike    Low expression in luminal epithelial
                       genes, genes expressed by adipose
                       tissue, other nonepithelial cell
                       types, and basal epithelial cells
Luminal A            ER[alpha] gene, GATA-binding protein 3,
                       X-box-binding protein 1, trefoil
                       factor 3, hepatocyte nuclear factor
                       3[alpha], and estrogen-regulated LIV-1
Luminal B            Low to moderate expression of luminal-specific
                       genes, including the ER
                       cluster

Abbreviations: ER, estrogen receptor; ERBB2, v-erb-b2 erythroblastic
leukemia viral oncogene homolog 2, neuro/glioblastoma-derived oncogene
homolog (avian); GRB7, growth factor receptor-bound protein 7.
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