The persisting puzzle of racial disparity in triple negative breast cancer: looking through a new lens
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors and absence of amplification of human epidermal growth factor receptor (HER2). This disease has no approved treatment with a poor prognosis particularly in African-American (AA) as compared to European-American (EA) patients. Gene ontology analysis showed specific gene pathways that are differentially regulated and gene signatures that are differentially expressed in AA as compared to EA. Such differences might underlie the basis for the aggressive nature and poor prognosis of TNBC in AA patients. In-depth studies of these pathways and differential genetic signature might give significant clues to improve our understanding of tumor biology associated with AA TNBC to advance the prognosis and survival rates. Along with gene ontology analysis, we suggest that post-translational modifications (PTM) could also play a crucial role in the dismal survival rate of AA TNBC patients. Further investigations are necessary to explore this terrain of PTMs to identify the racially disparate burden in TNBC.
Triple Negative Breast Cancer, Post Translational Modification, Racial Disparity, Gene Expression, Pathways, Review
Triple-negative breast cancer (TNBC), a subtype of breast cancer (BC), accounts for 15-20% of all BC diagnoses in the US. It has been recognized that women of African descent are twice as likely to develop TNBC than women of European descent (1). As the name foretells, TNBCs lack estrogen, progesterone, and human epidermal growth factor receptors. Unfortunately, TNBCs are defined by what they “lack” rather than what they “have” and thus this negative nomenclature provides no actionable information on “druggable” targets. Aptly, this particular BC subtype has no FDA-approved targeted therapies thus far, and the survival rate is dismal (2-5).
Primarily, TNBC patients exhibit higher resistance to chemotherapy than hormone receptor (HR) positive BCs (6). TNBC patients, whose tumors metastasize to visceral organs, survive only for a year. Thus, diagnosis of metastatic TNBC is necessarily a death sentence for patients (6). The heterogeneous tumor biology, aggressive clinical course, and higher metastatic potential underscore an unmet need to understand the molecular pathways and signaling circuitries that could be targeted in TNBC to develop effective novel molecules to ultimately improve its prognosis (7) (Figure 1). Literature reports several targeted molecular therapies for TNBC that have shown promising results. These novel agents include small molecule inhibitors that specifically target poly-ADP-ribose-polymerase (PARP-1) (8, 9), epidermal growth factor receptor (EGFR) (10, 11), multi-tyrosine kinases (12, 13), as well as anti-angiogenic agents (14, 15). A study by Sparano JA et al., pointed out a distinct molecular signature; ~70% of genes related to kinase activity, cell division, proliferation, DNA repair, anti-apoptosis, and transcriptional regulation are differentially expressed in TNBC vs. non-TNBC subtype (16). This review focuses on racially-distinct differential gene expression signatures in TNBC and how these distinct features may provide insights into the mechanistic basis for aggressive TNBC and offer cues about druggable target space in racially diverse TNBC patients. More importantly, we offer a new perspective to look at racial disparities through the lens of post-translational modifications of key molecules.
3. Dissecting the TNBC racially disparate burden
3.1. Does race influence TNBC onset and progression?
TNBC in AA women present higher mortality rates compared to women of European descent. The major contributing factors for such disparity are barriers to early screening, advanced disease stage at diagnosis, socio-demographic factors, socio-economic status, and lack of access to the healthcare treatment (17). AA premenopausal women exhibit a higher incidence and mortality rate compared to EA counterparts. However, postmenopausal women, do not show such a racial disparity (4, 18), suggesting that TNBC is significantly associated with younger age women of African descent (5).
Differences in survival outcomes among racially diverse TNBC patients remains controversial. Studies led by various groups such as Lund et al., (19) Bauer et al., (5) Carey et al., (20) and Sachdev et al., (21) have reported worse survival outcomes for women of African origin, after adjusting for socioeconomic factors, treatment delay, and tumor characteristics. Sachdev et al., showed that both unadjusted and stage-adjusted survival outcomes were better in EA over AA TNBC patients (21). On the other hand, other groups like Dawood et al., (22) O’ Brien et al., (23) and Sparano et al., (24) found no significant difference in survival outcomes between racially-distinct TNBC patients (4). Underlying these inconsistent results could be the nonuniformity of the biomarkers tested, lack of certainty of pathological parameters, lack of availability of treatment information to deduce the survival outcomes, and failure to consider multiple factors such as stage, grade, poverty index, and other treatment related factors (19).
Recently, Ademuyiwa et al., reported a detailed mutational analysis of AA and EA TNBC patients comparing the mutational landscape between the racially-distinct patient populations. Interestingly, they found no compelling differences in the panorama of mutated genes between AA and EA TNBC patients. Also, they found no racial differences between AA and EA TNBC patients in high prevalence genes (TP53, PI3CA, MLL3), attributed to the fact that there is no significant difference in somatic mutations of these genes (25). Collectively, these findings suggest that the aggressive disease course seen among AA TNBC patients may be independent of the dysregulation in common tumor growth promoting pathways. It is likely that there may be hitherto unknown biomarkers that offer an enhanced understanding of the racial divide in TNBC outcomes.
Studies above suggest that the TNBC incidence and mortality rates are higher in AA compared to EA, even after adjusting for clinical and socioeconomic variables that might explain the differential outcome among the races (17). Thus, it is tempting to speculate that intrinsic biological factors might be responsible for the racially disparate burden of TNBC. In this lieu, it has been shown that TNBC patients of African descent harbor a higher prevalence of the basal-like-1 tumor phenotype which is characterized by enhanced proliferation and sensitivity to chemotherapy (17). AA women with TNBC tumors demonstrate a higher rate of invasion, distant metastasis (7.37% vs. 4.67%, p=0.05), angiogenesis and cell growth compared to their EA counterparts (26). Thus, proteins/biomarkers that are differentially expressed among the races and are involved in pathways associated with cell cycle regulation, epithelial-mesenchymal transition (EMT), and angiogenesis may hold the key to understanding therapeutically druggable targets to minimize the disparity gap. Indeed, selective inhibitors for specific pathways, which are in overdrive or underdrive, merit exploration to delineate a precise molecular mechanism of aggressiveness that is significantly associated with AA TNBC patients.
3.2. Tumor microenvironment in TNBC and racial disparity
Tumor cells do not live in isolation, rather they create a favorable niche known as tumor microenvironment (TME) to enhance the crosstalk with various other cells. Apart from tumor cells, TME is comprised of immune cells, fibroblasts, lymphocytes, signaling molecules, and tumor vasculature proteins. TME supports the growth, angiogenesis and metastasis of tumor cells (54). It has been reported that TME significantly influences the malignant behavior and is crucial for reprogramming the surrounding cells in TNBC. Myriad of available literature suggest that tumor infiltrating lymphocytes (TILs) are critical in regulating TNBC microenvironment. Elevated number of T regulatory cells (Tregs) in TME has been correlated with poor prognosis in many types of cancers including TNB (55, 56). Our unpublished data demonstrate a higher fraction of TILs in AA over EA TNBCs, suggesting that TME plays an essential role in racially disparate TNBC population. Moreover, vast majority of literature shed light on various TME related molecules (CXCL12, CXCR4, VEGF, Resistin, MCP1, MMP2, MMP-9, SOS1, PSPHL, uPA, IL6, RASSF1A, etc.) that are significantly up-regulated in AA over EA BC (57). These molecules along with their precise molecular action warrants further investigations to delineate the aggressive tumor biology associated with AA TNBC. Previously, various groups have reported that tougher extracellular matrix (ECM) was efficient in blocking the crosstalk between the cells. However, the recent data have suggested that stiffer the tumor stroma, more aggressive the breast cancer subtype is likely to be (55, 58). Thus, increased ECM rigidity might contribute in altering the mechano-signaling, tumor vasculature and pro-tumorigenic infiltration and thereby provide clues about highly invasive AA tumor phenotype over EA in TNBC. A detailed study characterizing the differential TME associated with AA and EA TNBC might give further insights into the TNBC racial disparity and could improve the prognosis of AA TNBC patients.
3.3. Differential gene signatures and pathways in racially distinct TNBC
Although various research groups have developed several small molecule inhibitors and antibodies against cell cycle pathway components, none to date have shown full clinical translation (27). It is imperative to understand the intrinsic tumor biology, heterogeneity and molecular basis of TNBC in AA women to improve their prognosis and identify novel therapeutic targets. Thus, investigating tumor suppressor proteins and oncogenes having differential expression profile between AA and EA TNBC patients represents an advantageous strategy, as explored in this section.
Various studies have demonstrated that the breast tumor microenvironment varies between AA and EA TNBC patients (25, 28, 29). Recently, published data from our laboratory, Ogden A et al., have demonstrated that nuclear (n) KIFC1 is a poor prognosis marker in AA TNBC compared to EA TNBC. In this multi-institutional study, we evaluated the expression of nKIFC1 in 163 AA and 144 EA TNBC patients using immunohistochemistry. Our data suggest that KIFC1 is an essential biomarker required for migration of AA TNBC tumor. High nKIFC1 weighed index (WI) was significantly related to worse overall survival (OS), progression-free survival (PFS) and high distant metastasis-free survival (DMFS) in AA but not EA TNBC (30). Using microarray analysis, Ademuyiwa et al., identified the top twenty upregulated genes in AA TNBC patients, including CRYBB2, FAM3A, CROCCL1, SCXB, PIF1, TRABD, TSPO, C6orf108, MIIP, C21orf70, TOP1MT, NACA2, PWP2, and BAX compared to EA TNBC patients. AA women have higher p53 gene mutations and lower PI3CA mutations over EA patients (25). Using laser capture microdissection, Martin et al., (28) analyzed genome-wide mRNA expression specific to tumor epithelium and stroma in AA and EA BC patients. Theirs and other related studies demonstrated upregulation of a panel of genes including CDKN2A, CCNA2, CCNB1, CCNE2, TMPO, AFMR, PSPHL, CXCL10, CXCL11, VEGF, syndecan-1, AURKB, CDCA5, CENPM, DDX11, and MK767 in AA TNBC patients compared to EA patients (28, 31, 32). It may be worthwhile to conduct validation studies to confirm the battery of genes or a “gene signature” that can stratify racially-distinct tumors and predict their risk of metastasis. Indeed, additional in vitro and in vivo experiments are warranted to reconcile the gene expression-based findings.
Even though TNBC incidence is higher in AA, several reports pinpoint significantly lower incidence of BRCA1 germline mutations in AA over EA TNBC, suggesting that other genetic mechanisms beyond germline BRCA1 mutation may explain the aggressive disease course in AA TNBC patients (33, 34). Genome-wide association studies (GWAS) showed that AA women have a higher frequency of risk variant at telomerase reverse transcriptase (TERT)-CLPTM1-like locus on chromosome 5p15 (odds ratio (OR)=1.25, p=1.1*10-9) (35). A genetic variant in the LOC643714 gene is associated with 23% increased risk for TNBC in AA but not in EA TNBC (OR=1.23, 95% confidence interval) (36). Gene expression profiles revealed higher expression of IGF1R, VEGF, and nuclear EZH2 in women with AA decent than in women with EA decent (17). Recent genomic and transcriptomic analyses revealed a loss of RB1 expression in ~20% TNBC patients. This RB1 loss is significantly related to higher sensitivity towards gamma irradiation, doxorubicin, and methotrexate therapy (37). Thus, RB1 status, and the molecular network upstream and downstream of RB1 in AA and EA TNBC separately are pivotal to gain insights into pathways that confer chemo resistance in racially diverse TNBC population. While LOXL2 and SNCG are novel prognostic markers studied in TNBC EMT, invasion and metastasis (38, 39), these markers merit an in-depth investigation in the context of racial disparity in TNBC to obtain essential clues about metastasis and poor survival in AA TNBC. A prostaglandin is producing the enzyme, Cox-2, is involved in cancer cell proliferation, anti-apoptosis, angiogenesis and invasion (40, 41). Dhakal et al., (41) found that Cox-2 expression is positively correlated with poor prognosis in TNBC than in non-TNBC patients. This study suggests a prognostic value of Cox-2 in TNBC, and thus, it is of significance to evaluate and validate its role within the racially diverse TNBC population.
3.4. Our Perspective: Looking racial disparity through a new lens
Using Next-Generation Sequencing (NGS) data from The Cancer Genome Atlas (TCGA), we analyzed several gene signatures in AA and EA TNBC. Surprisingly, we only found a few genes that showed a considerable difference in expression at the mRNA or protein level in AA and EA TNBC. These data indicated that the molecular basis of disparity might not be restricted to just the gene/protein expression based intrinsic tumor biology. It is well appreciated that protein diversity stemming due to alternative mRNA splicing or post-translational modifications (PTM) play vital roles in the modulation of cellular functions and protein-protein/protein-lipids crosstalks (42). PTMs are linked with a myriad of biological processes such as cell proliferation (43), differentiation (43), organismal development (44) and in the progression of human diseases including cancer (45). Advances in proteomics have critically fueled investigations into PTMs to reveal that these generate a complex combinatorial code regulating gene expression and protein functions, and whose deregulation has been documented in various types of cancers (46). PTMs at the molecular level amounts to altering the physical and chemical properties of proteins—in most cases reversibly—and in turn dictate their interaction with other cellular components such as protein, cell membranes, and DNA. Examples of PTMs, highly relevant in the context of cancer, include phosphorylation, acetylation, lipidation, sumoylation, methylation, and glycosylation which rewire the oncogenic signaling pathways in response to various stimuli surprisingly including tumor microenvironment, nutrient status, and hypoxia (47). The current status on the role of PTMs states that the pattern of post-translational modifications is a better predictive biomarker than the changes in total protein level and gives an additional layer of complexity by fine-tuning downstream signaling events (48). Thus, it is highly tempting to speculate that mapping of the PTMs patterns with the genomic and proteomic profile is likely to serve as a next-generation biomarker for improved prognosis of the disease, simultaneously providing a protein network framework amenable for therapeutic targeting in a spatiotemporal fashion.
Befittingly, a tantalizing possibility that may explain the TNBC disparity beyond differences at the gene and protein expression level is a differential profile of PTMs. Recent data by Golavilli PN et al., have shown that in TNBC, AMP-activated protein kinases (AMPK) activates glycogen synthase kinase 3 beta (GSK3β) and Sirtuin 1(SIRT1) by inhibiting phosphorylation at Ser9 and Ser47, respectively. This activation of GSK3β and SIRT1, in turn, inhibit the upregulation of metadherin (MTDH) and suppresses TNBC cell proliferation (49). Hanigan TW et al., have evidenced that c-Jun N-terminal kinase (JNK) mediated histone deacetylase 3 (HDAC3) phosphorylation in TNBC cells is essential for HDAC inhibitor binding and selectivity (50). These studies collectively suggest a non-trivial role of PTMs in TNBC. However, to the best of our knowledge, there is no study showing that PTMs might be one of the factors responsible for the underlying TNBC racial disparity. Our unpublished data suggest that PTMs (phosphorylation, acetylation, and sumoylation) may account for the disproportionately higher burden of TNBC in AA population and concomitantly may shed light on the aggressive nature of AA TNBC compared with EAs. This space of post-translational regulation is an uncharted terrain and presents an attractive avenue that merits extensive and intensive exploration to address racial disparity in TNBC.
Indeed, the cumulative effect of multiple genes and their underlying molecular pathways define the tumor phenotype. However, to date, there are very limited therapeutic options, mainly because of the paucity of in-depth knowledge about the intrinsic tumor biology of AA and EA TNBC. Identifying enrichment of biological networks in the tumor epithelium and tumor stroma might help to stratify the AA and EA TNBC patients and improve treatment regimen. Gene expression profiles suggested that tumor angiogenesis and chemotaxis pathway are functionally different between AA and EA BC patients (51-53). These pathways and underlying genes associated with these need to be evaluated in detail to understand the racial disparity in TNBC. We have performed a gene ontology (GO) analysis to trace out the genes and gene pathways that might be differentially regulated in AA and EA TNBC. Our analysis revealed the top ten gene pathways that are significantly up and down-regulated in AA and EA TNBC. The top five pathways that are up-regulated in AA TNBC include, i. Hematopoietic or lymphoid organ development (GO:0048534, p=0.0004), ii. Leukocyte differentiation (GO:0002521, p=0.00046), iii. Hemopoiesis (GO:0030097, p=0.0005), iv. Immune effector process (GO:0002252, p=0.00060), v. Lymphocyte differentiation (GO:0030098, p=0.00066). The top five pathways that are downregulated in AA TNBC over EA are i. Post-translational protein modification (GO:0043687, p=0.000494), ii. Homophilic cell adhesion (GO:0007156, p=0.00089), iii. Glycosylation (GO:0070085, p=0.00192), iv. Protein glycosylation (GO:0006486, p=0.0020), v. Macromolecule Glycosylation (GO:0043413, p=0.0020). The gene signatures associated with these up and down-regulated pathways must be studied to evaluate the precise molecular mechanism of action that can improve the trajectory of AA TNBC tumor biology and may give pointers on the aggressive disease course in AA TNBC over EA. Differentially expressed genes in AA TNBC can be found in Table 1. Future in-depth studies would be decisive in addressing the precise molecular regulation associated with the genes and pathways mentioned above to delineate the disparate tumor burden in AA TNBC. The landscape of molecular players that are differentially regulated at the transcriptional, post-transcriptional, translational or post-translational level may be the “next thing” to investigate to deconvolve the complexities surrounding TNBC racial disparity and might offer mechanistic cues that can directly translate to improve the prognosis and survival of AA TNBC patients.
|Gene symbol||Gene name||Gene symbol||Gene name|
|KLK14||kallikrein-related peptidase 14||STON1-GTF2A1L||STON1-GTF2A1L readthrough|
|RETN||resistin||FAM83A||family with sequence similarity 83 member A|
|TREML4||triggering receptor expressed on myeloid cells like 4||NEFH||neurofilament heavy polypeptide|
|NACA2||nascent polypeptide-associated complex alpha subunit 2||DEFB1||defensin beta 1|
|UPK3B||uroplakin 3B||GNG4||G protein subunit gamma 4|
|KRT8P41||keratin 8 pseudogene 41||MUCL1||mucin like 1|
|HAPLN1||hyaluronan and proteoglycan link protein 1||NPTX2||neuronal pentraxin 2|
|TCTE1||t-complex-associated-testis-expressed 1||ADGRL3||adhesion G protein-coupled receptor L3|
|JSRP1||junctional sarcoplasmic reticulum protein 1||ENDOU||endonuclease, poly (U) specific|
|CCL3L1||C-C motif chemokine ligand 3 like 1||GPAT2||glycerol-3-phosphate acyltransferase 2, mitochondrial|
|KLK10||kallikrein-related peptidase 10||CAMP||cathelicidin antimicrobial peptide|
|MYEOV||myeloma overexpressed||FAIM2||Fas apoptotic inhibitory molecule 2|
|PPP1R14A||protein phosphatase 1 regulatory inhibitor subunit 14A||EYA1||EYA transcriptional coactivator and phosphatase 1|
|ACOXL||acyl-CoA oxidase-like||SYTL5||synaptotagmin like 5|
|LEFTY1||left-right determination factor 1||CYP2B7P||cytochrome P450 family 2 subfamily B member 7, pseudogene|
|SYCE1||synaptonemal complex central element protein 1||FGL1||fibrinogen like 1|
|CCDC154||coiled-coil domain containing 154||EPGN||epithelial mitogen|
|LAIR2||leukocyte-associated immunoglobulin-like receptor 2||ST8SIA2||ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2|
|CSDC2||cold shock domain containing C2||FREM2||FRAS1 related extracellular matrix protein 2|
|DHDH||dihydrodiol dehydrogenase||AKR1B15||aldo-keto reductase family 1 member B15|
|AZU1||azurocidin 1||FABP6||fatty acid binding protein 6|
|FGF17||fibroblast growth factor 17||IGF2||insulin like growth factor 2|
|WNT6||Wnt family member 6||PRLR||prolactin receptor|
|BMP2||bone morphogenetic protein 2||TUBA3D||tubulin alpha 3d|
|FBXO2||F-box protein 2||FIGN||fidgetin, microtubule severing factor|
|MEF2B||myocyte enhancer factor 2B||NA||NA|
|C1QL2||complement C1q like 2||CLCA2||chloride channel accessory 2|
|MZB1||marginal zone B and B1 cell specific protein||AR||androgen receptor|
|LRRC14B||leucine rich repeat containing 14B||RERGL||RERG like|
|TSGA10IP||testis specific 10 interacting protein||PHEX||phosphate regulating endopeptidase homolog, X-linked|
|PRKY||protein kinase, Y-linked, pseudogene||HTR1B||5-hydroxytryptamine receptor 1B|
|DCST2||DC-STAMP domain containing 2||NCAM2||neural cell adhesion molecule 2|
|CLIC3||chloride intracellular channel 3||NLGN1||neuroligin 1|
|ART3||ADP-ribosyltransferase 3||SLC7A2||solute carrier family 7 member 2|
|RNF112||ring finger protein 112||HOXA11||homeobox A11|
|MAPK15||mitogen-activated protein kinase 15||BEX1||brain expressed X-linked 1|
|AARD||alanine and arginine rich domain containing protein||ENPP3||ectonucleotide pyrophosphatase/phosphodiesterase 3|
|FOXF2||forkhead box F2||FUT6||fucosyltransferase 6|
|ACTN3||actinin alpha 3 (gene/pseudogene)||NA||NA|
|CDHR1||cadherin related family member 1||ATP2B2||ATPase plasma membrane Ca2+transporting 2|
|SP7||Sp7 transcription factor||CLLU1OS||chronic lymphocytic leukemia up-regulated 1 opposite strand|
|KLK11||kallikrein related peptidase 11||DCX||doublecortin|
|FOXH1||forkhead box H1||NRG3||neuregulin 3|
|NKX2-3||NK2 homeobox 3||TENM2||teneurin transmembrane protein 2|
|FAM222A-AS1||FAM222A antisense RNA 1||NRXN3||neurexin 3|
|KRT3||keratin 3||TNR||tenascin R|
|P2RX1||purinergic receptor P2X 1||NKAIN1||Na+/K+transporting ATPase interacting 1|
|TUBB8||tubulin beta 8 class VIII||CYP4F22||cytochrome P450 family 4 subfamily F member 22|
|WNT2B||Wnt family member 2B||TMEM246||transmembrane protein 246|
|CAMKV||CaM kinase like vesicle associated||RIMKLA||ribosomal modification protein rimK like family member A|
|CALML6||calmodulin like 6||PKIB||protein kinase (cAMP-dependent, catalytic) inhibitor beta|
|LGR6||leucine rich repeat containing G protein-coupled receptor 6||DSG1||desmoglein 1|
|KISS1||KiSS-1 metastasis-suppressor||ZMAT4||zinc finger matrin-type 4|
|FOXQ1||forkhead box Q1||TRPA1||transient receptor potential cation channel subfamily A member 1|
|CNBD2||cyclic nucleotide binding domain containing 2||SH3GL2||SH3 domain containing GRB2 like 2, endophilin A1|
|ICAM5||intercellular adhesion molecule 5||PCP4||Purkinje cell protein 4|
|KRT38||keratin 38||STC1||stanniocalcin 1|
|TMPRSS5||transmembrane protease, serine 5||HCRTR2||hypocretin receptor 2|
|SLC22A20||solute carrier family 22 member 20||ELAVL3||ELAV like RNA binding protein 3|
|RADIL||Rap associating with DIL domain||AFF3||AF4/FMR2 family member 3|
|FOLR3||folate receptor 3||CA3||carbonic anhydrase 3|
A multitude of genes and their underlying molecular pathways define the tumor phenotype. Within the TNBC subtype, tumor phenotype is distinct among the women from African decent vs. the one with European descent, and thus AA women exhibit poor survival and prognosis. To date, there are very limited therapeutic options, mainly because of the intrinsic tumor biology of AA and EA TNBC is not clear. Thus, a landscape of molecular players that are differentially regulated at transcription, post-transcription, translation or post-translation level may be beneficial to investigate the TNBC racial disparity and might help to improve the prognosis and survival of AA TNBC patients. Identifying enrichment of biological networks in the tumor epithelium and tumor stroma might help to stratify the AA and EA TNBC patients and improve treatment regimen. Gene expression profiles suggested that tumor angiogenesis and chemotaxis pathway are functionally different between AA and EA TNBC patients. These pathways and underlying genes associated with these need to be evaluated in detail to understand the racial disparity in TNBC. Thus, there is an unmet need to determine the molecular players and their underlying mechanism of action to improve the AA TNBC prognosis and survival.
The authors are thankful to Ms. Nikita Wright for the constructive criticisms and thorough analytical reading of the manuscript.
1. J. H. Silber, P. R. Rosenbaum, A. S. Clark, B. J. Giantonio, R. N. Ross, Y. Teng, M. Wang, B. A. Niknam, J. M. Ludwig, W. Wang, O. Even-Shoshan and K. R. Fox: Characteristics associated with differences in survival among black and white women with breast cancer. JAMA, 310(4), 389-397 (2013)
5. K. R. Bauer, M. Brown, R. D. Cress, C. A. Parise and V. Caggiano: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer, 109(9), 1721-8 (2007)
6. F. Kassam, K. Enright, R. Dent, G. Dranitsaris, J. Myers, C. Flynn, M. Fralick, R. Kumar and M. Clemons: Survival Outcomes for Patients with Metastatic Triple-Negative Breast Cancer: Implications for Clinical Practice and Trial Design. Clinical Breast Cancer, 9(1), 29-33 (2009)
8. F. Poggio, M. Bruzzone, M. Ceppi, B. Conte, S. Martel, C. Maurer, M. Tagliamento, G. Viglietti, L. Del Mastro, E. de Azambuja and M. Lambertini: Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis. ESMO Open, 3(4), e000361 (2018)
11. A. A. Changavi, A. Shashikala and A. S. Ramji: Epidermal Growth Factor Receptor Expression in Triple Negative and Nontriple Negative Breast Carcinomas. Journal of Laboratory Physicians, 7(2), 79-83 (2015)
12. E. Caldas-Lopes, L. Cerchietti, J. H. Ahn, C. C. Clement, A. I. Robles, A. Rodina, K. Moulick, T. Taldone, A. Gozman, Y. Guo, N. Wu, E. de Stanchina, J. White, S. S. Gross, Y. Ma, L. Varticovski, A. Melnick and G. Chiosis: Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proceedings of the National Academy of Sciences of the United States of America, 106(20), 8368-8373 (2009)
13. R. S. Finn, J. Dering, C. Ginther, C. A. Wilson, P. Glaspy, N. Tchekmedyian and D. J. Slamon: Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/”triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Research and Treatment, 105(3), 319-326 (2007)
14. B. K. Linderholm, H. Hellborg, U. Johansson, G. Elmberger, L. Skoog, J. Lehtiö and R. Lewensohn: Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Annals of Oncology, 20(10), 1639-1646 (2009)
16. J. A. Sparano, L. J. Goldestin, B. H. Childs, S. Shak, S. Badve, F. L. Baehner, N. E. Davidson, G. W. S. Jr. and R. Gray: Genotypic characterization of phenotypically defined triple-negative breast cancer. Journal of Clinical Oncology, 27(15_suppl), 500-500 (2009)
17. E. C. Dietze, C. Sistrunk, G. Miranda-Carboni, R. O’Regan and V. L. Seewaldt: Triple-negative breast cancer in African-American women: disparities versus biology. Nature reviews. Cancer, 15(4), 248-254 (2015)
19. M. J. Lund, K. F. Trivers, P. L. Porter, R. J. Coates, B. Leyland-Jones, O. W. Brawley, E. W. Flagg, R. M. O’Regan, S. G. A. Gabram and J. W. Eley: Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA. Breast Cancer Research and Treatment, 113(2), 357-370 (2009)
20. L. A. Carey, C. M. Perou, C. A. Livasy, L. G. Dressler, D. Cowan, K. Conway, K. G., M. A. Troester, C. K. Tse, S. Edmiston, S. L. Deming, J. Geradts, M. C. Cheang, T. O. Nielsen, P. G. Moorman, H. S. Earp and R. C. Millikan: Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA, 295(21), 2492-2502 (2006)
21. J. C. Sachdev, S. Ahmed, M. M. Mirza, A. Farooq, L. Kronish and M. Jahanzeb: Does Race Affect Outcomes in Triple Negative Breast Cancer? Breast Cancer : Basic and Clinical Research, 4, 23-33 (2010)
22. S. Dawood, K. Broglio, S.-W. Kau, M. C. Green, S. H. Giordano, F. Meric-Bernstam, T. A. Buchholz, C. Albarracin, W. T. Yang, B. T. J. Hennessy, G. N. Hortobagyi and A. M. Gonzalez-Angulo: Triple Receptor–Negative Breast Cancer: The Effect of Race on Response to Primary Systemic Treatment and Survival Outcomes. Journal of Clinical Oncology, 27(2), 220-226 (2009)
23. K. M. O’Brien, S. R. Cole, C.-K. Tse, C. M. Perou, L. A. Carey, W. D. Foulkes, L. G. Dressler, J. Geradts and R. C. Millikan: Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study. Clinical cancer research : an official journal of the American Association for Cancer Research, 16(24), 6100-6110 (2010)
24. J. A. Sparano, M. Wang, F. Zhao, V. Stearns, S. Martino, J. A. Ligibel, E. A. Perez, T. Saphner, A. C. Wolff, G. W. Sledge, W. C. Wood and N. E. Davidson: Race and Hormone Receptor–Positive Breast Cancer Outcomes in a Randomized Chemotherapy Trial. JNCI Journal of the National Cancer Institute, 104(5), 406-414 (2012)
25. F. O. Ademuyiwa, Y. Tao, J. Luo, K. Weilbaecher and C. X. Ma: Differences in the mutational landscape of triple negative breast cancer in African Americans and Caucasians. Breast cancer research and treatment, 161(3), 491-499 (2017)
26. M. S. Hamid, R. Shameem, A. Pudusseri, R. Graham, D. Shani and K. M. Sullivan: Racial/ethnic disparities in clinicopathologic features and treatment modalities of triple-negative breast cancer in black premenopausal women. Journal of Clinical Oncology, 32(26_suppl), 58-58 (2014)
28. D. N. Martin, B. J. Boersma, M. Yi, M. Reimers, T. M. Howe, H. G. Yfantis, Y. C. Tsai, E. H. Williams, D. H. Lee, R. M. Stephens, A. M. Weissman and S. Ambs: Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients. PLoS ONE, 4(2), e4531 (2009)
29. S. Kalla Singh, Q. W. Tan, C. Brito, M. De León and D. De León: Insulin-like growth factors I and II receptors in the Breast Cancer Survival Disparity among African-American Women. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 20(3), 245-254 (2010)
30. A. Ogden, C. Garlapati, X. Bill) Li, R. C. Turaga, G. Oprea, N. Wright, S. Bhattarai, K. Mittal, C. Sonmez Wetherilt, U. Krishnamurti, M. Reid, M. Jones, M. Gupta, R. Osan, S. Pattni, A. Riaz, S. Klimov, A. Rao, G. Cantuaria and R. Aneja: Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer. (2017)
31. S. S. Kalla, Q. W. Tan, C. Brito, M. De León and D. De León: Differential Insulin-like Growth Factor II (IGF-II) Expression: A Potential Role for Breast Cancer Survival Disparity. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 20(2), 162-170 (2010)
32. R. Lindner, C. Sullivan, O. Offor, K. Lezon-Geyda, K. Halligan, N. Fischbach, M. Shah, V. Bossuyt, V. Schulz, D. P. Tuck and L. N. Harris: Molecular Phenotypes in Triple Negative Breast Cancer from African American Patients Suggest Targets for Therapy. PLoS ONE, 8(11), e71915 (2013)
33. R. Nanda, L. Schumm, S. Cummings, J. D. Fackenthal, L. Sveen, F. Ademuyiwa, M. Cobleigh, L. Esserman, N. M. Lindor, S. L. Neuhausen and O. I. Olopade: Genetic testing in an ethnically diverse cohort of high-risk women: A comparative analysis of brca1 and brca2 mutations in american families of european and african ancestry. JAMA, 294(15), 1925-1933 (2005)
35. C. A. Haiman, G. K. Chen, C. M. Vachon, F. Canzian, A. Dunning, R. C. Millikan, X. Wang, F. Ademuyiwa, S. Ahmed, C. B. Ambrosone, L. Baglietto, R. Balleine, E. V. Bandera, M. W. Beckmann, C. D. Berg, L. Bernstein, C. Blomqvist, W. J. Blot, H. Brauch, J. E. Buring, L. A. Carey, J. E. Carpenter, J. Chang-Claude, S. J. Chanock, D. I. Chasman, C. L. Clarke, A. Cox, S. S. Cross, S. L. Deming, R. B. Diasio, A. M. Dimopoulos, W. R. Driver, T. Dünnebier, L. Durcan, D. Eccles, C. K. Edlund, A. B. Ekici, P. A. Fasching, H. S. Feigelson, D. Flesch-Janys, F. Fostira, A. Försti, G. Fountzilas, S. M. Gerty, I. The Gene Environment, C. Breast Cancer in Germany, G. G. Giles, A. K. Godwin, P. Goodfellow, N. Graham, D. Greco, U. Hamann, S. E. Hankinson, A. Hartmann, R. Hein, J. Heinz, A. Holbrook, R. N. Hoover, J. J. Hu, D. J. Hunter, S. A. Ingles, A. Irwanto, J. Ivanovich, E. M. John, N. Johnson, A. Jukkola-Vuorinen, R. Kaaks, Y.-D. Ko, L. N. Kolonel, I. Konstantopoulou, V.-M. Kosma, S. Kulkarni, D. Lambrechts, A. M. Lee, L. Le Marchand, T. Lesnick, J. Liu, S. Lindstrom, A. Mannermaa, S. Margolin, N. G. Martin, P. Miron, G. W. Montgomery, H. Nevanlinna, S. Nickels, S. Nyante, C. Olswold, J. Palmer, H. Pathak, D. Pectasides, C. M. Perou, J. Peto, P. D. P. Pharoah, L. C. Pooler, M. F. Press, K. Pylkäs, T. R. Rebbeck, J. L. Rodriguez-Gil, L. Rosenberg, E. Ross, T. Rüdiger, I. d. S. Silva, E. Sawyer, M. K. Schmidt, R. Schulz-Wendtland, F. Schumacher, G. Severi, X. Sheng, L. B. Signorello, H.-P. Sinn, K. N. Stevens, M. C. Southey, W. J. Tapper, I. Tomlinson, F. B. L. Hogervorst, E. Wauters, J. Weaver, H. Wildiers, R. Winqvist, D. Van Den Berg, P. Wan, L. Y. Xia, D. Yannoukakos, W. Zheng, R. G. Ziegler, A. Siddiq, S. L. Slager, D. O. Stram, D. Easton, P. Kraft, B. E. Henderson and F. J. Couch: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer. Nature Genetics, 43(12), 1210-1214 (2011)
36. E. A. Ruiz-Narváez, L. Rosenberg, Y. C. Cozier, L. A. Cupples, L. L. Adams-Campbell and J. R. Palmer: Polymorphisms in the TOX3/LOC643714 locus and risk of breast cancer in African-American women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 19(5), 1320-1327 (2010)
37. T. J. W. Robinson, J. C. Liu, F. Vizeacoumar, T. Sun, N. Maclean, S. E. Egan, A. D. Schimmer, A. Datti and E. Zacksenhaus: RB1 Status in Triple Negative Breast Cancer Cells Dictates Response to Radiation Treatment and Selective Therapeutic Drugs. PLoS ONE, 8(11), e78641 (2013)
38. S. G. Ahn, S. M. Dong, A. Oshima, W. H. Kim, H. M. Lee, S. A. Lee, S.-h. Kwon, J.-h. Lee, J. M. Lee, J. Jeong, H.-D. Lee and J. E. Green: LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. Breast Cancer Research and Treatment, 141(1), 89-99 (2013)
39. G. Moreno-Bueno, F. Salvador, A. Martín, A. Floristán, E. P. Cuevas, V. Santos, A. Montes, S. Morales, M. A. Castilla, A. Rojo-Sebastián, A. Martínez, D. Hardisson, K. Csiszar, F. Portillo, H. Peinado, J. Palacios and A. Cano: Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO Molecular Medicine, 3(9), 528-544 (2011)
41. H. Prasad Dhakal, B. Naume, M. Synnestvedt, E. Borgen, R. Kaaresen, E. Schlichting, G. Wiedswang, A. Bassarova, R. Holm, K.-E. Giercksky and J. M Nesland: Expression of cyclooxygenase-2 in invasive breast carcinomas and its prognostic impact. (2012)
42. C. T. Walsh, S. Garneau-Tsodikova and G. J. Gatto: Protein Posttranslational Modifications: The Chemistry of Proteome Diversifications. Angewandte Chemie International Edition, 44(45), 7342-7372 (2005)
45. A. Eisenberg-Lerner, A. Ciechanover and Y. Merbl: Post-translational modification profiling – A novel tool for mapping the protein modification landscape in cancer. Experimental Biology and Medicine, 241(14), 1475-1482 (2016)
48. A. Martín-Bernabé, C. Balcells, J. Tarragó-Celada, C. Foguet, S. Bourgoin-Voillard, M. Seve and M. Cascante: The importance of post-translational modifications in systems biology approaches to identify therapeutic targets in cancer metabolism. Current Opinion in Systems Biology, 3, 161-169 (2017)
49. P. N. Gollavilli, A. K. Kanugula, R. Koyyada, S. Karnewar, P. K. Neeli and S. Kotamraju: AMPK inhibits MTDH expression via GSK3β and SIRT1 activation: potential role in triple negative breast cancer cell proliferation. The FEBS Journal, 282(20), 3971-3985 (2015)
50. T. W. Hanigan, S. M. Aboukhatwa, T. Y. Taha, J. Frasor and P. A. Petukhov: Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity. Cell Chemical Biology, 24(11), 1356-1367.e8 (2017)
53. L. Bingle, N. J. Brown and C. E. Lewis: The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. The Journal of Pathology, 196(3), 254-265 (2002)
56. L. de la Cruz-Merino, A. Barco-Sánchez, F. Henao Carrasco, E. Nogales Fernández, A. Vallejo Benítez, J. Brugal Molina, A. Martínez Peinado, A. Grueso López, M. Ruiz Borrego, M. Codes Manuel de Villena, V. Sánchez-Margalet, A. Nieto-García, E. Alba Conejo, N. Casares Lagar and J. Ibáñez Martínez: New insights into the role of the immune microenvironment in breast carcinoma. Clinical & developmental immunology, 2013, 785317-785317 (2013)
57. S. K. Deshmukh, S. K. Srivastava, N. Tyagi, A. Ahmad, A. P. Singh, A. A. L. Ghadhban, D. L. Dyess, J. E. Carter, K. Dugger and S. Singh: Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings. Carcinogenesis, 38(8), 757-765 (2017)