Abstract
Molecular classification of breast cancer (BC) identified diverse subgroups that encompass distinct biological behavior and clinical implications, in particular in relation to prognosis, spread, and incidence of recurrence. Basal-like breast cancers (BLBC) compose up to 15% of BC and are characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification with expression of basal cytokeratins 5/6, 14, 17, epidermal growth factor receptor (EGFR), and/or c-KIT. There is an overlap in definition between triple-negative BC and BLBC due to the triple-negative profile of BLBC. Also, most BRCA1-associated BCs are BLBC, triple negative, and express basal cytokeratins (5/6, 14, 17) and EGFR. There is a link between sporadic BLBC (occurring in women without germline BRCA1 mutations) with dysfunction of the BRCA1 pathway. Despite the molecular and clinical similarities, these subtypes respond differently to neoadjuvant therapy. BLBCs are associated with an aggressive phenotype, high histological grade, poor clinical behavior, and high rates of recurrences and/or metastasis. Their molecular features render these tumors especially refractory to anti-hormonal-based therapies and the overall prognosis of this subset remains poor. In this article, the molecular profile, genomic, and epigenetic characteristics as well as BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC are presented, with emphasis on the discordant findings in current literature.
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Introduction
Breast cancer (BC) is one of the most common human malignancies, accounting for 22% of all cancers in women worldwide. The incidence rate is higher in North America, Europe, and Australia compared to other regions including Africa and Southern and Eastern Asia [1]. Although the incidence remains high, the decrease of the overall mortality has been attributed to advances in early detection and therapeutic modalities [2]. BC represents a complex and heterogeneous disease that comprises distinct pathologies, histological features, and clinical outcome. Current knowledge of BC etio-pathology, biology, and treatment protocols has benefited from the simultaneous analysis of multiple biomarkers. In particular, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2) are the predictive markers utilized to identify a high-risk phenotype and for selection of the most efficient therapies [3, 4].
Gene microarray profiling of human breast carcinomas has categorized invasive breast carcinomas into five distinct subtypes; luminal A, luminal B, normal breast-like, human epithelial growth factor receptor-2 (HER2) overexpressing, and basal-like breast cancer (BLBC) [1]. The unfavorable prognosis as well as the lack of effective targeted therapy makes BLBC the subject of intensive research. The present review summarizes current knowledge in molecular profiling, genomic and epigenetic characteristics, BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC (Fig. 1). Emphasis is given to the discordant findings in the literature.
Classification of BC
The striking heterogeneity of BC in terms of tumor histology, clinical presentation, and response to treatment has been analyzed at the molecular level by gene-expression profiling, which has revealed that each breast tumor has its own unique molecular portrait, providing the basis for an improved molecular taxonomy of this disease [5, 6]. BC is classified into major BC subtype signatures: ER-positive and ER-negative groups, which can be further subdivided into additional subgroups with distinct biological and clinical significance [7] (Fig. 2).
Approximately 75% of BCs are ER and/or PR positive [8]. The ER-positive tumors express ER, PR, ER-responsive genes, and other genes that encode typical proteins of luminal epithelial cells so they are termed “luminal group.” This group is subdivided in luminal A and B tumors, depending on the level of proliferation-related genes and/or HER2/ERBB2 [7, 8]. Luminal A subgroup is characterized by the high expression of ERα gene, GATA binding protein 3 (GATA3), B-cell CLL/lymphoma 2 (BCL2), luminal cytokeratin 8 (CK8), CK18, X-box binding protein, trefoil factor 3, hepatocyte nuclear factor 3α, estrogen-regulated LIV-1, ERBB3, and ERBB4, whereas luminal B group showed low to moderate expression of the luminal-specific genes including ER-clusters (Fig. 2) [7, 8].
The second broad group, the ER-negative tumors, comprises 20–25% of BC and is further subdivided into three subgroups: HER2-positive, BLBC, and normal breast-like (Fig. 2) [7–9]. HER2 positive tumors express high levels of HER2 and genes related to the HER2 amplicon [2, 7]. The normal breast-like signature defines a group of tumors with high expression of genes of adipose cells and other non-epithelial cell types, as well as low levels of luminal markers [5]. However, molecular classification of this group subtypes remains partially understood and subject of debates. Finally, tumors belonging to the basal-like subgroup express high levels of basal/myoepithelial markers, such as CK 5/14/17 and laminin, and do not express ER, PR, and HER2 and hence they are referred to as triple negative (TN) [4].
Basal-like breast cancer is a distinct group of tumors. They represent from 8 up to 37% of all BC cases, depending on the proportion of grade III cases included in the populations studied [10]. BLBC presents frequent mutations in the TP53 gene, evidence of genomic instability, and inactivation of the Rb pathway [11]. Notably, it was initially assumed that the cell of origin of this tumor subtype was found in the stem cells of the basal compartment. Recent gene-expression profiling of the different subpopulations in human normal mammary gland and analysis of tumors with basal-like features showed that BLBC phenotype appears to be more similar to the gene signature derived from the luminal progenitor population [12].
All of these BC subtypes were named to reflect the gene-expression patterns of two principal epithelial cell types of the normal adult breast, namely the luminal epithelial cells, which form a single cell layer lining in the lumen of the duct or lobule, and surface or basal myoepithelial cells, which form a second cell layer surrounding the luminal cells and are in direct contact with the basement membrane [8]. They are associated with markedly different clinical outcomes, ranging from the good prognosis ER-positive luminal A tumors to the poor prognosis ER-negative HER2 and BLBC tumors; these could be used as prognostic marker with respect to overall and relapse-free survival in a subset of patients that had received uniform therapy [6, 7].
Herschkowitz et al. [13] described a potential new subtype, referred as “claudin-low.” Claudin-low group are TN. This subtype is characterized by low expression of genes involved in tight junctions and cell–cell adhesion, including Claudins 3, 4, 7, Occludin, and E-cadherin [9, 13, 14] and shows high expression of epithelial-to-mesenchymal transition (EMT) genes and stem cell features [15, 16]. Currently, it has been reported that patients with claudin-low tumors have poor clinical outcomes and some studies are focusing on their association with BLBC to identify treatment sensitivity to specific chemotherapeutics and/or targeted agents.
A new class of BC called “molecular apocrine tumors” has been suggested for BC based on increased expression of androgen receptor (AR) [17, 18]. These tumors have some morphological hallmarks of apocrine tumors but there are no strict pathological criteria for diagnosis as classical apocrine carcinomas such as overexpression but not amplification of HER2 [17]. Immunohistochemically, these tumors are ER- and PR-negative and AR-positive. It was observed that almost all ER-positive tumors also express AR; however, the expression of AR in ER-negative group is predominantly observed in the HER2-positive subtype. On the other hand, a few TN tumors can also express AR and its expression seems to be related to apocrine differentiation. Indeed, AR-related targeted therapy was proposed for BC, especially for ER-negative/AR-positive tumors [2, 8].
Molecular profile of BLBC
Basal-like breast cancers express genes characteristic of basal/myoepithelial cells [2]. They showed no expression of ER- and PR-responsive genes, and other genes characteristic of luminal epithelial cells of the normal breast as well as genes located on the HER2 amplicon [11]. Moreover, BLBC tumors show an overexpression of epidermal growth factor receptor (EGFR), CK-5, -6, -14, and -17, vimentin, p-cadherin, fascin, caveolins 1 and 2, αβ-crystallin, and EGFR [2, 19]. There are also other potentially relevant features including mutated TP53 and BRCA1 genes and deregulated immune response genes [11]. Manié et al. (2009) demonstrated that TP53 was frequently mutated in both BRCA1 (97%) and sporadic BLBC (92%). However, the rate of complex mutations, such as insertion/deletion was found higher in BRCA1-BLBC than in sporadic BLBC (42 and 9%, respectively). c-KIT expression is also higher in BLBC [9, 19, 20]. Nielsen et al. [19] observed that c-KIT expression was more common in basal-like tumors than in other BC but did not influence prognosis [19]. These authors suggested an immunohistochemical panel of four antibodies (ER, HER1, HER2, and CK-5/6) that could identify BLBC with 100% specificity and 76% sensitivity. However, other studies in BLBC have found different staining patterns of the basal keratins (CK-5/6 and especially CK-17, -8/-18) in part due to difficulty to detect by immunohistochemical methods focal and often weak reactivity [21, 22]. There are several reported biomarkers associated with BLBC as well as putative candidates suitable for immunohistochemical screening (Table 1) [10, 11, 23], however, currently, there is no specific international consensus on complement biomarkers that can define BLBC.
Deregulated integrin expression has also been detected in BLBC and may contribute to aggressive cell behaviors and progression seen in this subtype. Several basal-like gene products are important structural elements of basal epithelial cell such as the extracellular matrix (ECM) receptor α6β4 integrin, subunits of laminin-5 (an ECM ligand of α6β4 integrin), and bullous pemphigoid antigen (BPAG1). These proteins are components of hemidesmosomes specialized adhesive structures that anchor basal epithelial cells to the ECM via basal CK intermediate filament network (Table 2) [2, 6]. These alterations can be related to the biologically aggressive phenotype of these TN tumors although this remains to be established in order to better guides current efforts to develop meaningful targeted approaches.
Several genes related to BLBC have been implicated in promoting cellular proliferation, cell survival, and cell migration and invasion [8]. Despite the wide diversity of signaling pathways involved in these processes, signaling molecules such as the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3-kinase)-AKT, and nuclear factor-kB (NF-kB) are commonly deregulated as seen in other BC subtypes [2, 6]. A representative subset of gene regulation and function in BLBC are indicated in Table 2.
Other alterations such as Wnt pathway activation has been observed in BLBC [24]. This study reported cytoplasmic and nuclear accumulation of β-catenin in BLBC, and suggested that β-catenin could be a valuable therapeutic target for this subtype [24]. Nevertheless there is strong evidence of stabilization of β-catenin protein in a majority of human breast tumors, and mouse model systems clearly demonstrate that activated Wnt signaling can promote mammary tumorigenesis [25].
Even though BLBC has similar characteristic with other breast tumor subgroups, several large studies provided evidence that BLBC, per se, is an independent adverse prognostic factor, in spite of the fact that approximately 10% of BLBC patients have a good prognosis [26]. Clearly more studies are required to establish how common and often overlapping cell signaling pathways can contribute to histological and biological heterogeneity and progression to metastasis. Nevertheless, gene-expression profiling of BLBC provides a myriad of candidate genes that might selectively contribute to the aggressive phenotype of these tumors and emerging evidence strongly support a breast stem-like cell as a precursor for these tumors [2, 6, 9, 27].
Potential biomarkers were presented in this table only if the positivity percentage in BLBC was above 30% and at least twice as high as in non-BLBC (Table 2).
Genomic profiling of BLBC
It was by the advent and use of high-throughput molecular profiling methods for the study of BC that was brought to the forefront the existence of the so-called BLBC, which has distinct and aggressive clinicopathological characteristics. This subgroup present a greater genetic complexity compared with other BC subtypes, suggesting a greater degree of genetic instability [28, 29]. Bergamaschi et al. [30] found that BLBC show the highest frequency of DNA losses and gains compared with others subtypes and also reported that despite of the highest prevalence of genomic aberrations, BLBC show less genomic amplifications than tumors pertaining to other molecular subgroups [10, 28, 30].
Copy number aberrations (CNAs) are distributed throughout the genome in BLBC resulting in a sawtooth pattern, which is similar to that seen in BRCA1-associated hereditary BC [31], such as a frequent loss of 5q, being that BRCA1-modifier locus for hereditary BC penetrance has been mapped to 5q [30]. Chromosomal regions 8p12, 8q24, 11q13, 17q12, and 20q13 are recurrently amplified in BC in general [32]. However, some particular recurrent amplifications described in BLBC are approximately two to three times higher than the other subtypes [10, 28] and it includes 7p11.2 involving the region of EGFR, 7q31 affecting caveolin 1, and 12p13 being the amplifications of 8p12 and 17q11.2 associated with poor outcomes [32]. Adélaïde et al. [33] observed rare high-level amplifications in basal tumors affecting small regions, including PIK3CA (3q26), IGF1R (15q26), and CCNE1 (19q11-12), but also single genes, such as EGFR (7p11), FGFR2 (10q26), and BCL2L2 (14q11). EGFR, FGFR2, and IGF1R are tyrosine kinase receptors with a broad mitogenic and angiogenesis function and thus can serve as potential therapeutic targets. The existence of these amplifications and such high degree of heterogeneity in BC, even within a given subtype, confirms that molecular profiling will be paramount to select the appropriate treatment. In the same line, specific genomic losses were also detected in basal subtype. The loss of heterozygosity (LOH) at 4p and 5q has been able to define a subclass of BLBC [33, 34]. Losses of 4p and 5q associated with BLBC targeted several genes including candidate or known tumor suppressing genes such as SLIT2 (4p15.31), GPR125 (4p15.31), RASA1 (5q14.3), and APC (5q22.2) [33]. Hence, the aim of these efforts in genomic studies is to understand the function of these markers in mammary oncogenesis and progression and to develop therapeutic approaches against critical markers adapted to various molecular categories of tumors.
Epigenetic changes of BLBC
Breast cancer development depends on both genetic alterations and epigenetic changes involving DNA methylation and histone modifications [35]. Roll et al. [36] reported a methylation signature in BLBC. BLBC express a hypermethylator phenotype that is characterized by concurrent methylation-dependent silencing of CEACAM6, CDH1, CST6, ESR1, LCN2, and SCNN1A genes that are involved in a wide range of neoplastic processes relating to tumors with poor prognosis [36]. ESR1 (encodes for the ERα) and CDH1 (encodes for the E-cadherin) are concurrently methylated in BC and both can regulate tumor progression [37]. Tumors with CDH1 and ESR1 methylation were associated with significantly lower hormone receptor levels, younger age at diagnosis, and TP53 mutations [38]. Recently Holm et al. [39] showed that ARGDIBI, GRB7, and SEMA3B are also methylated in BLBC [39].
Some authors found equally distributed methylation events at specific genes among different histological subsets of neoplasms suggesting that a CpG island methylator phenotype does not occurs in BC [40]. Otherwise, Dumont et al. [41] proposed that DNA methylation profiles observed in BC may reflect the history of environmental exposures based on the induction of p16/Rb pathway and impact on epigenetic changes resulting from methylation of CpG islands associated with tumorigenesis [36, 41]. Elsheik et al. [42] described a variation in global levels of histone markers in BC. Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and K4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in BLBC and HER2-positive tumors and were related with adverse prognosis [42]. Alterations in histone methylation and demethylation are likely critical steps in neoplastic progression by disrupting the normal stem- or progenitor-cell program [35]. Further studies are needed involving BLBC and DNA methylation machinery to fully understand the clinicopathological implications of the hypermethylator phenotype in primary BC and subtypes for better diagnosis and improved treatment strategies.
BLBC and BRCA1
Several large and integrative research studies based on expression and copy number profiling of familial BC demonstrated molecular heterogeneity of these tumors similar to sporadic tumors, as well these studies defined molecular subtypes based on markers other than BRCA1 and BRCA2 germline status [11, 43, 44]. Microarray or immunohistochemical analyses demonstrated that approximately three quarters of BRCA1-related BC are BLBC, whereas BRCA2 tumors generally cluster within the luminal A or B groups [43–46] and non-BRCA1/2 with luminal A tumors [11, 44].
BRCA1-related BLBC are TN and frequently positive for Ki67, basal CKs (CK5/6, CK14), TP53, EGFR, P-cadherin [44, 47] and with frequent X-chromosome abnormalities [6]. Interesting, the clinical outcomes for women with BLBC and BRCA1-related BC are broadly similar in particular for early (within 5 years) relapse and pattern of metastatic spread.
Several investigators have been exploring the role of the BRCA1 pathway in sporadic BLBC, even if not all BC arising in BRCA1 mutation carriers are TN or BLBC [11]. Although it is not clear whether BRCA1 inactivation is the cause or consequence of a BLBC phenotype, Rakha et al. [47] suggested two hypotheses for the similarities between BLBC and tumors arising in BRCA1 mutation carriers: (i) the precursor cells of BLBC may be more tolerant to loss of BRCA1 function than those of other BC subtypes, possibly because of the phenotype of the cell at the initiating event or the concurrent inactivation of other tumor suppressor genes, such as TP53; and alternatively, (ii) BRCA1 may be involved in the differentiation of breast epithelial cells and, therefore, BRCA1 inactivation would lead to tumors with a stem cell-like phenotype. Although the aforementioned hypotheses are attractive, there is no definitive answer at present time. In fact, there are increasingly more coherent data to suggest that BRCA1 pathway dysfunction may play an important role in development of not only familial but also sporadic BC tumors [47].
Decreased BRCA1 transcript levels and nuclear protein expression have indeed been observed in BLBC. In addition, BRCA1 promoter hypermethylation has been reported in metaplastic BC (a rare type of BLBC) and overexpression of ID4 (a negative regulator of BRCA1 expression) was shown in sporadic BLBC [29]. Furthermore, Gorski et al. [48] showed that siRNA-mediated inhibition of BRCA1 up-regulates genes associated with the BLBC phenotype, suggesting that loss of BRCA1 expression may contribute to the development of BLBC [48]. The characteristics of hereditary BRCA1-associated BC found in sporadic BLBC cancers have thus been termed “BRCA-ness” with potential clinical implications [11].
More studies are needed to better characterize the profile of BRCA1-mutated BLBC based on genomic, epigenomic, and proteomic analyses in order to pinpointing novel candidate cancer genes in this particular BC subtype.
Clinicopathological features of BLBC
Basal-like breast cancers are associated with high histological and nuclear grade, poor tubule formation, the presence of central necrotic or fibrotic zones, pushing borders, conspicuous lymphocytic infiltrate, and typical/atypical medullary features with exceptionally high mitotic and proliferative indices [1, 11]. Most of these tumors are infiltrating ductal tumors with solid growth pattern, aggressive clinical behavior, and high rate of metastasis to the brain and lung. Unlike other BC subtypes, there seems to be no correlation between tumor size and lymph node metastasis in BLBC [1, 11, 49]. The most common histological type of BLBC is invasive ductal carcinoma, however, BLBC also involves some unique histological types including invasive lobular, medullary, metaplastic, myoepithelial, neuroendocrine, apocrine, adenoid cystic, and secretory breast carcinoma [50]. BLBC constitutes a different clinical entity associated with worse clinical outcome [7, 11].
Some interesting correlations have been found in the literature. BLBC showed a significantly higher incidence in premenopausal African-American patients (20–27%) compared to Caucasian woman (10–16%) [50, 51]. A large part of the racial difference in the distribution of BLBC may be attributable to different distribution of specific risk factors. The use of oral contraceptives in women <40 years old, younger age at diagnosis, hispanic ethnicity, lower socio-economic status, with abdominal adiposity and metabolic syndrome were also shown to significantly increase risk of BLBC [50, 52] (Table 3). Interestingly, as shown on Table 3, some of the principal risk factors of BLBC are opposite to those observed for BC (Luminal A).
Therapeutic considerations
Basal-like breast cancers are particularly enigmatic because the genes that are responsible for their aggressive phenotype are not well understood, and this constitutes a major barrier to develop targeted therapies for this group. The urgent necessity for new therapies is underscored by the fact that BLBC do not express ER or HER2 and thus are typically refractory to endocrine therapy and to trastuzumab, a humanized monoclonal antibody that targets HER2 [6, 28].
Nevertheless, as BRCA1 pathway may be deficient in BLBC, these tumors may respond to specific therapeutic regimens, such as the currently available inhibitors of the poly (ADP-ribose) polymerase (PARP) enzyme. Cells deficient in BRCA1 have indeed a defect in DNA double strand break repair that could render them particularly sensitive to chemotherapy drugs that generate DNA double strand breaks, such as inhibitors of PARP enzyme [53]. However, as stated above, not all BLBC are associated with BRCA1 inactivation [54].
Epidermal growth factor receptor could also represent a therapeutic target as it is often overexpressed in BLBC. Recently, Dong et al. [55] identified Notch pathway as one compensatory mechanism leading to resistance to EGFR inhibition in BLBC, providing additional insights and potential strategies to overcome resistance, and rendering dual-pathway inhibition a viable clinical strategy that can be tested in the near term of BLBC [55].
Finally, research on tumor stem cells may guide the search for better therapeutic approaches such as by targeting cell surface markers or signaling pathways activated in cancer-stem cells. These exciting concepts are currently taken a greater priority in therapeutic drug discovery research [1].
Conclusions
Current research on BC molecular profiling and classification has generated exciting impetus to ongoing efforts to deepen our basic understanding of the complex biology of BLBC. The exciting progress is not without challenges owing in part to technology issues. For instance, a more accurate identification of BLBC requires to determine the immunohistochemical sensitivity and specificity of some of biomarkers addressed in this article, including in relation to the size of the study cases, antibody specificity toward protein isoforms. Also, exploring a more comprehensive hypermethylation profile, it can be useful for understanding the expression of genes involved tumorigenesis, hallmarks process and tumor progression of BC, especially BLBC. Currently, BLBC lack any specific targeted therapy and the identification of new markers and therapeutic targets in relevant preclinical models and then in human trials are urgently needed before meaningful therapeutic outcomes could be achieved.
References
Haupt B, Ro JY, Schwartz MR (2010) Basal-like breast carcinoma: a phenotypically distinct entity. Arch Pathol Lab Med 134:130–133
Rakha EA, El-Sayed ME, Green AR et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32
Presson AP, Yoon NK, Bagryanova L et al (2011) Protein expression based multimarker analysis of breast cancer samples. BMC Cancer. doi:10.1186/1471-2407-11-230
Weigelt B, Reis-Filho JS (2010) Molecular profiling currently offers no more than tumour morphology and basic immunohistochemistry. Breast Cancer Res. doi:10.1186/BCR2734
Perou CM, Sørlie T, Eisen MB et al (2000) Molecular portraits of human breast tumour. Nature 406:747–752
Yehiely F, Moyano JV, Evans JR et al (2006) Deconstructing the molecular portrait of basal-like breast cancer. Trends Mol Med 12(11):537–544
Sørlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874
Niemeier LA, Dabbs DJ, Beriwal S et al (2010) Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 23:205–212
Irvin WJ Jr, Carey LA (2008) What is triple-negative breast cancer? Eur J Cancer 44:2799–2805
Rakha EA, Elsheikh SE, Aleskandarany MA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15:2302–2310
Schneider BP, Winer EP, Foulkes WD et al (2008) Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 14:8010–8018 Review
Gastaldi S, Comoglio PM, Trusolino L (2010) The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res. doi:10.1186/BCR2617
Herschkowitz JI, Simin K, Weigman VJ et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. doi: 10.1186/gb-2007-8-5-r76
Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K et al (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69:4116–4124
Prat A, Parker JS, Karginova O et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. doi:10.1186/BCR2635
Herschkowitz JI, Zhao W, Zhang M et al (2011) Breast cancer special feature: comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. Proc Natl Acad Sci USA. doi:10.1073/pnas.1018862108
Farmer P, Bonnefoi H, Becette V et al (2005) Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24:4660–4671
Lopez-Garcia MA, Geyer FC, Lacroix-Triki M et al (2010) Breast cancer precursors revisited: molecular features and progression pathways. Histopathology 57:171–192
Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374
Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423
Böcker W, Bier B, Freytag G et al (1992) An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part I: normal breast and benign proliferative lesions. Virchows Arch A Pathol Anat Histopathol 421:315–322
Korsching E, Packeisen J, Agelopoulos K et al (2002) Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Investig 82:1525–1533
Choo JR, Nielsen TO (2010) Biomarkers for basal-like breast cancer. Cancers 2:1040–1065
Khramtsov AI, Khramtsova GF, Tretiakova M et al (2010) Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 176:2911–2920
Turashvili G, Bouchal J, Burkadze G et al (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223
Rubovszky G, Udvarhelyi N, Horváth Z et al (2010) Triple-negative breast carcinoma—review of current literature. Magy Onkol 54:325–335 Review
Honeth G, Bendahl PO, Ringnér M et al (2008) The CD44+/CD24− phenotype is enriched in basal-like breast tumors. Breast Cancer Res. doi:10.1186/BCR2108
Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26:2568–2581 Review
Kwei KA, Kung Y, Salari K et al (2010) Genomic instability in breast cancer: pathogenesis and clinical implications. Mol Oncol 4:255–256
Bergamaschi A, Kim YH, Wang P et al (2006) Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45:1033–1040
Toft DJ, Cryns VL (2011) Minireview: basal-like breast cancer: from molecular profiles to targeted therapies. Mol Endocrinol 25:199–211 Review
Letessier A, Sircoulomb F, Ginestier C et al (2006) Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers. BMC Cancer. doi:10.1186/1471-2407-6-245
Adélaïde J, Finetti P, Bekhouche I et al (2007) Integrated profiling of basal and luminal breast cancers. Cancer Res 67:11565–11575
Wang ZC, Lin M, Wei LJ et al (2004) Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res 64:64–71
Liu F, Chen X, Allali-Hassan A et al (2009) Discovery of a 2, 4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 52:7950–7953
Roll JD, Rivenbark AG, Jones WD et al (2008) DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer. doi:10.1186/1476-4598-7-15
Parrella P, Poeta ML, Gallo AP et al (2004) Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors. Clin Cancer Res 10:5349–5354
Li S, Rong M, Iacopetta B (2006) DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett 237:272–280
Holm K, Hegardt C, Staaf J et al (2010) Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res. doi:10.1186/BCR2590
Bae YK, Brown A, Garrett E et al (2004) Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res 10:5998–6005
Dumont N, Wilson MB, Crawford YG et al (2008) Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 105:14867–14872
Elsheikh SE, Green AR, Rakha EA et al (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69:3802–3809
Van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536
Waddell N, Arnold J, Cocciardi S et al (2010) Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res Treat 123:661–677
Hedenfalk I, Ringner M, Ben-Dor A et al (2003) Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA 100:2532–2537
Sørlie T (2004) Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 40:2667–2675 Review
Rakha EA, Reis-Filho JS, Ellis IO (2008) Impact of basal-like breast carcinoma determination for a more specific therapy. Pathobiology 75:95–103
Gorski JJ, Kennedy RD, Hosey AM et al (2009) The complex relationship between BRCA1 and ERalpha in hereditary breast cancer. Clin Cancer Res 15:1514–1518
Ray PS, Wang J, Qu Y et al (2010) FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 70:3870–3876
Yamamoto Y, Iwase H (2010) Clinicopathological features and treatment strategy for triple-negative breast cancer. Int J Clin Oncol 15(4):341–351
Kobayashi S (2008) Basal-like subtype of breast cancer: a review of its unique characteristics and their clinical significance. Breast Cancer 15:153–158
Millikan RC, Newman B, Tse CK, Moorman PG et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109:123–139
Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134
Ismail-Khan R, Bui MM (2010) A review of triple-negative breast cancer. Cancer Control 17:173–176
Dong Y, Li A, Wang J et al (2010) Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res 70:5465–5474
Rodríguez-Pinilla SM, Sarrió D, Honrado E et al (2007) Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas. J Clin Pathol 60:1006–1012
Rodríguez-Pinilla SM, Sarrió D, Honrado E et al (2006) Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 12:1533–1539
Li H, Cherukuri P, Li N et al (2007) Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res 67:501–510
Parry S, Savage K, Marchiò C et al (2008) Nestin is expressed in basal-like and triple negative breast cancers. J Clin Pathol 61:1045–1050
Charafe-Jauffret E, Monville F, Bertucci F et al (2007) Moesin expression is a marker of basal breast carcinomas. Int J Cancer 121:1779–1785
Elsheikh SE, Green AR, Rakha EA et al (2008) Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer 99:327–334
Pinilla SM, Honrado E, Hardisson D et al (2006) Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat 99:85–90
Savage K, Lambros MB, Robertson D et al (2007) Caveolin 1 is overexpressed and basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, amplified in a subset of immunohistochemical, and in situ hybridization analysis. Clin Cancer Res 13:90–101
Savage K, Leung S, Todd SK et al (2008) Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis. Breast Cancer Res Treat 110:245–256
Lu S, Simin K, Khan A et al (2008) Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin Cancer Res 14:1050–1058
Reis-Filho JS, Steele D, Di Palma S et al (2006) Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue. Mod Pathol 19:307–319
Hasegawa M, Moritani S, Murakumo Y et al (2008) CD109 expression in basal-like breast carcinoma. Pathol Int 58:288–294
Matos I, Dufloth R, Alvarenga M et al (2005) p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 447:688–694
Paredes J, Lopes N, Milanezi F et al (2007) P-cadherin and cytokeratin 5: useful adjunct markers to distinguish basal-like ductal carcinomas in situ. Virchows Arch 450:73–80
Zabouo G, Imbert AM, Jacquemier J et al (2009) CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 11:R1
Klingbeil P, Natrajan R, Everitt G et al (2010) CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res Treat 120:95–109
Viale G, Rotmensz N, Maisonneuve P et al (2009) Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat 116:317–328
Mani SA, Yang J, Brooks M et al (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 104:10069–10074
Umemura S, Shirane M, Takekoshi S et al (2009) Overexpression of E2F-5 correlates with a pathological basal phenotype and a worse clinical outcome. Br J Cancer 100:764–771
Ribeiro-Silva A, Ramalho LN, Garcia SB et al (2005) p63 correlates with both BRCA1 and cytokeratin 5 in invasive breast carcinomas: further evidence for the pathogenesis of the basal phenotype of breast cancer. Histopathology 47:458–466
Rakha EA, Putti TC, Abd El-Rehim DM et al (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208:495–506
Herschkowitz JI, He X, Fan C et al (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75
Kuroda H, Ishida F, Nakai M et al (2008) Basal cytokeratin expression in relation to biological factors in breast cancer. Hum Pathol 39:1744–1750
Walter O, Prasad M, Lu S et al (2009) IMP3 is a novel biomarker for triple negative invasive mammary carcinoma associated with a more aggressive phenotype. Hum Pathol 40:1528–1533
Skaland I, Janssen EA, Gudlaugsson E et al (2009) The prognostic value of the proliferation marker phosphohistone H3 (PPH3) in luminal, basal-like and triple negative phenotype invasive lymph node-negative breast cancer. Cell Oncol 31:261–271
Zhang H, Rakha EA, Ball GR et al (2010) The proteins FABP7 and OATP2 are associated with the basal phenotype and patient outcome in human breast cancer. Breast Cancer Res Treat 121:41–51
Tang XY, Umemura S, Tsukamoto H et al (2010) Overexpression of fatty acid binding protein-7 correlates with basal-like subtype of breast cancer. Pathol Res Pract 206:98–101
Moyano JV, Evans JR, Chen F et al (2006) AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J Clin Invest 116:261–270
Sitterding SM, Wiseman WR, Schiller CL et al (2008) AlphaB-crystallin: a novel marker of invasive basal-like and metaplastic breast carcinomas. Ann Diagn Pathol 12:33–40
Acknowledgments
We would like to thank the regional counsel of Auvergne and Ligue Nationale contre le Cancer (Allier Committee).
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The authors declare that they have no conflict of interest.
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Valentin, M.D., da Silva, S.D., Privat, M. et al. Molecular insights on basal-like breast cancer. Breast Cancer Res Treat 134, 21–30 (2012). https://doi.org/10.1007/s10549-011-1934-z
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DOI: https://doi.org/10.1007/s10549-011-1934-z