| Abstract|| |
Introduction: Cancer stem cells (CSC) within the tumors play a central role in tumorigenesis. It is, thus, of utmost importance to identify these cells to develop effective cancer therapy. Triple-Negative Breast Cancer (TNBC) is an aggressive molecular subtype of breast cancer associated with poor patient outcomes. The role of CD44 immunohistochemistry (IHC) as a putative CSC in breast carcinomas, particularly of the TNBC-subtype is ambiguous, with equivocal results. Aims and Objectives: The present study aims to assess the role of CSC in breast carcinoma by immunohistochemical analysis of CD44 expression in TNBC. The association of TNBC expressing CSC with histological grade as well as with angiogenesis (using CD34 IHC) has been studied. Materials and Methods: Biopsy samples from 58 patients with infiltrating ductal carcinoma, NST were studied. The histology of the tumor was sub-classified into grades 1–3. Based on immunohistochemical analysis (ER, PR, HER2/Neu), the cases were divided into TNBC and NTNBC groups. The tissue sections were also subjected to analysis for CD44 to identify the CSC-phenotype and CD34 to evaluate angiogenesis, to determine the microvascular density (MVD). Results: Out of the 58 cases in the study, 28 were TNBC and 30 were NTNBC. CSC phenotype (CD44 positive) was expressed significantly higher in the TNBC (78%) versus the NTNBC (53%) (p-value 0.043). The MVD estimated using CD34 IHC was lower in the TNBC group in our study, though the difference was not statistically significant. A larger proportion of cases in TNBC showed a higher histological grade (35%) in comparison to NTNBC (27%). However, statistically, it was not significant. Conclusion: Our study demonstrated that CD44 as a CSC marker is seen significantly more in the TNBC category of invasive ductal carcinomas. Further large-scale studies, to confirm these findings, will be of potential therapeutic and prognostic value.
Keywords: Breast cancer, cancer stem cells, CD44, immunohistochemistry, TNBC
|How to cite this article:|
Tomar R, Rakheja G, Verma N, Thakur S, Khurana N, Ghuliani D. Role of CD44 as cancer stem cell marker in triple-negative breast cancer and its association with histological grade and angiogenesis. Indian J Pathol Microbiol 2023;66:258-63
|How to cite this URL:|
Tomar R, Rakheja G, Verma N, Thakur S, Khurana N, Ghuliani D. Role of CD44 as cancer stem cell marker in triple-negative breast cancer and its association with histological grade and angiogenesis. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Jun 3];66:258-63. Available from: https://www.ijpmonline.org/text.asp?2023/66/2/258/369086
| Introduction|| |
Breast cancer is the most commonly diagnosed cancer in females worldwide as well as the leading cause of cancer-related deaths. Diversity in breast cancer is known, with numerous histological and molecular subtypes being identified. Subtyping of breast cancer according to molecular and genetic subtypes has an impact on the prognostication of disease and selection of treatment modalities. Triple-negative breast cancer (TNBC) is known as a type of breast cancer in which there is a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). Targeted therapy is available for ER or PR positive as well as HER2 positive categories, but no standard treatment option is available for TNBC. Owing to a markedly poorer prognosis in this subset and lack of specific targeted therapy, much research is going on in this category of breast cancer.
Many studies have provided insights into the pathogenesis of neoplasms, with the identification of cancer stem cell (CSC) niches in tumors playing a central role in tumorigenesis. It is, thus, of paramount importance that these specific cells within the tumor are better-characterized to develop effective anticancer therapy. Various techniques have been developed to identify CSC. Immunohistochemical staining for stem cell markers such as CD44 allows excellent visualization of such cells.
While the literature is replete with numerous studies evaluating the role of CD44 immunohistochemistry (IHC) as a stem cell marker in various tumors, there is a paucity of literature evaluating its potential role in breast carcinoma, especially the TNBC, which are known to have a poor prognosis and survival.[3–18]
The present study aimed to gain better insight into the role of CSC in breast carcinoma by immunohistochemical analysis of CD44 expression in TNBC. The association of TNBC expressing CSC with histological grade as well as with angiogenesis (using CD34 IHC) has been studied.
| Materials and Methods|| |
This is a retrospective descriptive study including biopsy samples from 58 female patients with carcinoma breast, of no special type (NST). Histological types of invasive breast carcinoma apart from NST, like mucinous, lobular, and so on. were excluded from the study. Patients with prior neoadjuvant chemotherapy and/or radiation therapy and male patients with carcinoma breast were also excluded.
Detailed clinical history, examination findings, and radiological data were recorded from the existing data records. The paraffin-embedded tissues were sectioned and stained with routine Hematoxylin and Eosin using the standard protocol. Microscopic analysis of each specimen was done for confirmation of diagnosis as well as grading using the standard Elston/Nottingham modification of the Bloom Richardson grading system.
Cases diagnosed as infiltrating ductal breast carcinoma, NOS were subjected to immunohistochemical analysis for ER, PR, HER 2 neu (hormonal profile), CD44 (stem cell marker), and CD34 (for angiogenesis). About 4–5-μm thin sections were deparaffinized and rehydrated. To block the endogenous peroxide activity, the sections were placed in 3% hydrogen peroxide diluted in nine parts of methanol for 30 min. Target antigen retrieval was achieved using citrate buffer (pH 6.0) in the microwave. The sections were incubated overnight in a moist chamber with primary antibodies ER, PR, HER2/Neu, CD44, and CD34. The next day after bringing them to room temperature and washing, the secondary antibody (biotinylated anti-mouse polyclonal by Dako) was applied and the sections were re-incubated for 1 hour. Chromogen (Diaminobenzidine) was added for 1–3 min and checked under a microscope. Counterstaining was done with hematoxylin for 1 min.
Evaluation of Immunohistochemical expression
ER and PR:
The samples were considered positive for ER or PR if ≥1% of tumor cell nuclei were immunoreactive [Figure 1].
|Figure 1: (a) Nuclear positivity seen for ER (400x, IHC). (b) ER negative (200 x, IHC). (c) Nuclear positivity seen for PR (400 x, IHC). (d) PR negative (200 x, IHC). (e) Membranous positivity seen for HER2 (400 x, IHC). (f) HER2 negative (200 x, IHC)|
Click here to view
Reporting Her2neu was done as per the standard criteria.
IHC 3+ (strongly positive) tumor displays complete, intense, circumferential, membranous staining in >10% of tumor cells [Figure 1].
IHC 2+: weak to moderate complete membrane staining observed in >10% of invasive tumor cells.
IHC 1+: incomplete faint membrane staining and within >10% of invasive tumor cells.
IHC 0: no staining observed or incomplete, faint/barely perceptible membrane staining within ≤10% of invasive tumor cells.
Based on ER, PR, and HER2Neu expression, breast cancer was categorized into TNBC (ER−, PR−, and Her2−) and NTNBC (ER + PR + HER2−, ER + PR − HER2−, ER − PR − HER2+, ER + PR + HER2+, ER + PR − HER2+, ER-PR + HER2- and ER-PR + HER2+) phenotypes.
Assessment of positivity or negativity for CD44 was performed semi-quantitatively from immunohistochemically stained sections of tumor samples from patients. Tumor cells were localized using 10x objective and the level of positivity was graded for CD44 staining as 0 (negative), 1 (mild), 2 (moderate), and 3 (strongly positive) [Figure 2]. Positive staining for CD44 was defined as minimum 2+ circumferential membranous staining in atleast 10% of the tumor cells., Only membranous staining in tumor cells is scored and included in our study; stromal or non-membranous staining is not included.
|Figure 2: CD44 immunostain (400 x, IHC). (a) Negative (b) 1+ (c) 2+ (d) 3+|
Click here to view
Estimation of microvascular density (MVD) using CD34.
The vascular endothelium was highlighted using CD34 immunostaining. Angiogenesis was measured by counting the CD34-labelled microvessels. Any endothelial cell cluster with or without lumen, clearly separated from adjacent microvessels, was counted as a distinct microvessel. Larger vessels, having a muscular wall, were excluded from this count [Figure 3].
|Figure 3: (a-c) Infiltrating ductal carcinoma, NST (Hematoxylin and Eosin stain; 100 x, 200 x and 400 x respectively). (d) CD34 immunostain highlights the microvessels (IHC, 200 X)|
Click here to view
Under low power objective, (100 x magnification) the areas with the highest density of vascular staining were identified as hotspots. Under higher magnification (400 x), the microvessel counting was done in five, non-repetitive, hotspot areas. Average MVD was calculated by dividing by the field area.
The results were tabulated and statistical analysis was done using Student's t-test to look for a correlation among the histological parameters and expression of ER, PR, HER2/Neu with CD44, and angiogenesis. A P value <0.05 was considered significant. SPSS (IBM SPSS Statistics for Windows, Version 25 Armonk, NY: IBM Corp.) was used for analysis.
| Results|| |
Out of the total 58 breast carcinoma cases in this study, 40 cases (69%) were histological grade 2 and 18 (31%) belonged to grade 3. Based on hormonal profile (ER, PR, HER2), 28 cases were TNBC and 30 were NTNBC. These cases were taken in a comparable number (28 vs. 30) in both groups for statistical purposes. CSC marker CD44 was expressed in 22/28 (78%) cases of Triple-negative receptor type of breast cancers (TNBC) and 16/30 (53%) in non-Triple negative receptor type of breast cancers (NTNBC). (p-value 0.043) [Table 1].
The MVD estimated using CD34 IHC was lower in the TNBC group (9.73/mm2 vs. 11.15/mm2) in contrast to NTNBC in our study, though the difference was not statistically significant [Table 2].
Though the majority of the TNBC as well as NTNBC cases belonged to grade 2 (64% and 73%, respectively), a larger proportion of cases in TNBC showed higher histological grade (35% in comparison to 27%). However, statistically, it was not significant [Table 3].
| Discussion|| |
TNBC is an immunohistochemically distinct group of breast cancers, which is defined by a negative expression of ER, PR, and HER2/Neu. Compared with other forms of breast cancer, TNBC is associated with a younger age at diagnosis, advanced stage, increased risk of, and poorer outcome. These are not responsive to conventional receptor-target therapies also. Owing to the prognostic and therapeutic impact, TNBC has acquired much scientific interest in recent years.
The role of CSC was first described in breast cancer by Al-hajj and his co-workers with the cell-membrane markers CD44 and CD24. The concept emphasizes the presence of a subpopulation of cells within tumors that propel tumorigenesis. CSC are also known as tumor-initiating cells (TIC), or cancer metastasis-initiating cells (CMICs). CSC are especially shown to exhibit unique growth abilities including self-renewal and differentiation potential. Identification of CSCs and establishing their role in the pathogenesis of neoplasm may play a pivotal role in developing CSC targeting treatment in the future.
CD44, CD133, and ALDH1 are the most widely searched cellular markers for the detection of CSC. CD44 is a transmembrane glycoprotein that is involved in cell–cell interactions, cell adhesion, and migration. Besides, it promotes EGFR-mediated pathways, consequently leading to tumor cell growth, tumor cell migration, and chemotherapy resistance in solid cancers. Literature shows CD44 to be a critical player in numerous tumors including colon cancer, prostate cancer, as well as squamous cell carcinoma of the head and neck region., In breast cancer, few studies are available evaluating the compelling role of CD44 immunohistochemistry. Accumulating evidence suggests that the breast cancer cells with CD44+ subpopulation express higher levels of preinvasive genes and have greater invasive potential.
The present study demonstrated that CD44 expression is significantly associated with TNBC phenotype (p-value <0.05). [Table 4] summarizes the CD44 expression by IHC, reported in various studies. Similar to the present study, Idowu et al. have concluded that the patients with TNBC had a significantly higher frequency of breast CSC phenotype (CD44+/CD24-/low). Furthermore, the correlation of CD44+ immune-expression with the aggressive clinical behavior of TNBC has also been highlighted in their paper. Paula et al. in 2016 evaluated triple immunohistochemistry (CD44, ALDH1, and Ki67) in their work on 16 normal, 54 non-malignant, and 155 malignant breast tissues. They established that the mean percentages of cells with CD44+, ALDH+, and Ki67-phenotype increased significantly from non-malignant lesions to high-grade ductal carcinomas in situ, however, decreased in invasive ductal carcinomas. Nevertheless, this phenotype was associated with distant metastasis in patients with ductal carcinomas of the breast. Some studies have also concluded the CD44+/CD24-status to be associated with basal-like molecular subtype Wang et al. concluded that CD44/CD24 status evaluated by double-staining IHC constitutes an independent prognostic factor for TNBC. Klingbeil et al., in their aCGH analysis on CD44 expression, concluded that it is particularly enriched in TNBC, which has the worst clinical prognosis and outcome.
|Table 4: Comparative table of CD44 staining results in various studies,,,,,,,,,,,,,,,|
Click here to view
The present study showed a greater proportion of TNBC to be demonstrating higher histological grade, and conceivably an extrapolatable poorer prognosis; but the correlation is statistically insignificant (p-value >0.05). Literature shows that TNBC is a heterogeneous group, and most TNBCs are high-grade invasive ductal carcinomas, but there is also a subset of TNBCs comprising histologically low-grade lesions whose clinical course and molecular features differ from the high-grade TNBC.,, A comprehensive meta-analysis conducted by Wang et al. including 16 studies on breast cancer patients also concluded that no association was observed between CD44 and histological grade complying with our findings.
Angiogenesis plays a central role in the neoplastic process, promoting tumor growth and metastasis. Assessment of tumor MVD as a marker of angiogenesis has been abundantly researched and the development of agents that inhibit tumor angiogenesis has been an active area of investigation. Observational studies have demonstrated that MVD is a prognostic factor in invasive breast cancer, whereas others reached the opposite conclusion. Few studies have reflected that MVD in both basal-like and TNBC is significantly higher than in non-basal-like and non-TNBC. In our study, the MVD in two comparison groups of breast carcinoma revealed an increase in MVD in the NTNBC group, which was, however, statistically insignificant (p-value >0.05). Our study has excluded post- chemo and radiotherapy specimens, because of which the MVD has been analyzed on trucut cores. As there is a marked heterogeneity in micro-vascularization in any tumor, perhaps a careful search for possible hotspots in larger resection specimens can provide more representative results.
Previous studies have suggested that CD44 expression is related to tumor invasion, metastasis, and tumor progression, but there is a lack of clarity in terms of its prognostic value due to conflicting results.,,, On the one hand, studies have found that CD44+ breast cell lines have invasive and metastatic properties, correlating with poorer prognosis.,, On the other hand, it has also been documented that loss of CD44 promoted metastasis, by some researchers. Consequently, there is a need for larger sample studies to answer the question of whether CD44 is a true prognostic marker of patients' outcomes or a predictive marker of sensitivity to therapy. Research insinuates that the use of monoclonal antibodies against CD44 may be a landmark therapeutic achievement for advanced malignancies. A lacuna in the present study is the lack of follow-up of the cases in terms of treatment and clinical outcome, which might have contributed to the prognostic value. Furthermore, the use of additional stem cell markers, in larger studies, might further add to their potential role in breast cancers.
| Conclusions|| |
The present study deduces that CD44 + phenotype is expressed significantly more in triple-negative receptor type of breast cancers. However, no statistically significant correlation was found with the histological grade or angiogenesis in breast carcinoma. With the potential therapeutic implication of CD44 (cancer stem cell) in TNBC, this study adds to the limited existing literature available and can lay the foundation for further larger studies to substantiate these findings.
Ethics statement by all authors
The study was granted an exemption by the institutional research ethics committee of Maulana Azad Medical College on the grounds of research involving the collection or study of existing data and diagnostic specimens vide (F.1/IEC/MAMC/83/01/2021/No. 330).
List of abbreviations (In alphabetical order)
- CMICS: Cancer Metastasis-Initiating Cells
- CSC: Cancer Stem Cell
- ER: Estrogen Receptor
- HER2: Human Epidermal Growth Factor Receptor 2
- IHC: Immunohistochemistry
- MVD: Microvascular Density
- NST: No Special Type
- PR: Progesterone Receptor
- TIC: Tumor-Initiating Cells
- TNBC: Triple-Negative Breast Cancer.
Financial support and sponsorship
This study received financial support from institute under intramural research project.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018;68:394–424.
Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Archives of Gynecology and Obstetrics 2015;293:247–69.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983–8.
Atkinson RL, Yang WT, Rosen DG, Landis MD, Wong H, Lewis MT, et al
. Cancer stem cell markers are enriched in normal tissue adjacent to triple-negative breast cancer and inversely correlated with DNA repair deficiency. Breast Cancer Res 2013;15:R77.
Louderbough JMV, Schroeder JA. Understanding the dual nature of CD44 in breast cancer progression. Mol Cancer Res 2011;9:1573–86.
Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 2005;11:1154-9.
Ali HR, Dawson SJ, Blows FM, Provenzano E, Pharoah PD, Caldas C. Cancer stem cell markers in breast cancer: Pathological, clinical and prognostic significance. Breast Cancer Res 2011;13:R118.
Bane A, Viloria-Petit A, Pinnaduwage D, Mulligan AM, O'Malley FP, Andrulis IL. Clinical-pathologic significance of cancer stem cell marker expression in familial breast cancers. Breast Cancer Res Treat 2013;140:195-205.
Kim HJ, Kim MJ, Ahn SH, Son BH, Kim SB, Ahn JH, et al
. Different prognostic significance of CD24 and CD44 expression in breast cancer according to hormone receptor status. Breast 2011;20:78-85.
Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C, Bakarakos P, et al
. The clinicopathologic and prognostic significance of CD44+/CD24(-/low) and CD44-/CD24+tumor cells in invasive breast carcinomas. Hum Pathol 2008;39:1096-102.
Wei W, Hu H, Tan H, Chow LW, Yip AY, Loo WT. Relationship of CD44+CD24-/low breast cancer stem cells and axillary lymph node metastasis. J Transl Med 2012;10(Suppl 1):S6.
Qiao GL, Song LN, Deng ZF, Chen Y, Ma LJ. Prognostic value of CD44v6 expression in breast cancer: A meta-analysis. Onco Targets Ther 2018;11:5451-57.
Idowu MO, Kmieciak M, Dumur C, Burton RS, Grimes MM, Powers CN, et al.
CD44(+)/CD24(-/low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum Pathol 2012;43:364-73.
McFarlane S, Coulter JA, Tibbits P, O'Grady A, McFarlane C, Montgomery N, et al
. CD44 increases the efficiency of distant metastasis of breast cancer. Oncotarget 2015;6:11465-76.
Wang Z, Wang Q, Wang Q, Wang Y, Chen J. Prognostic significance of CD24 and CD44 in breast cancer: A meta-analysis. Int J Biol Markers 2017;32:e75-82.
Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, et al
. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: An early step necessary for metastasis. Breast Cancer Res 2006;8:R59.
Honeth G, Bendahl PO, Ringnér M, Saal LH, Gruvberger-Saal SK, Lövgren K, et al
. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res 2008;10:R53.
Currie MJ, Beardsley BE, Harris GC, Gunningham SP, Dachs GU, Dijkstra B, et al
. Immunohistochemical analysis of cancer stem cell markers in invasive breast carcinoma and associated ductal carcinoma in situ: Relationships with markers of tumor hypoxia and microvascularity. Hum Pathol 2013;44:402-11.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 1991;19:403-10.
Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, et al
. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP Guideline Update. J Clin Oncol 2020;38:1346-66.
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al
. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 2018;142:1364-82.
Pitule P, Cedikova M, Daum O, Vojtisek J, Vycital O, Hosek P, et al
. Immunohistochemical detection of cancer stem cell related markers CD44 and CD133 in metastatic colorectal cancer patients. Biomed Res Int 2014;2014:432139.
Sharma S, Sharma MC, Sarkar C. Morphology of angiogenesis in human cancer: A conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology 2005;46:481-9.
Cho SH, Park YS, Kim HJ, Kim CH, Lim SW, Huh JW, et al
. CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion. Int J Oncol 2012;41:211-8.
Thapa R, Wilson GD. The importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int 2016;2016:2087204.
Zheng Z, Shao N, Weng H, Li W, Zhang J, Zhang L, et al
. Correlation between epidermal growth factor receptor and tumor stem cell markers CD44/CD24 and their relationship with prognosis in breast invasive ductal carcinoma. Med Oncol 2015;32:275.
Cruz Paula ADA, Marques O, Sampaio R, Rosa A, Garcia J, Rêma A, et al
. Characterization of CD44+ALDH1+Ki-67- cells in non-malignant and neoplastic lesions of the breast. Anticancer Res 2016;36:4629-38.
Li W, Ma H, Zhang J, Zhu L, Wang C, Yang Y. Unraveling the roles of CD44/CD24 and ALDH1 as cancer stem cell markers in tumorigenesis and metastasis. Sci Rep 2017;7:13856.
Wang H, Wang L, Song Y, Wang S, Huang X, Xuan Q, et al
. CD44+/CD24- phenotype predicts a poor prognosis in triple-negative breast cancer. Oncol Lett 2017;14:5890-8.
Klingbeil P, Natrajan R, Everitt G, Vatcheva R, Marchio C, Palacios J, et al
. CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res Treat 2010;120:95-109.
Ribatti D, Nico B, Ruggieri S, Tamma R, Simone G, Mangia A. Angiogenesis and antiangiogenesis in triple-negative breast cancer. Transl Oncol 2016;9:453-7.
Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res 2005;65:6755-63.
Aulmann S, Waldburger N, Penzel R, Andrulis M, Schirmacher P, Sinn HP. Reduction of CD44(+)/CD24(-) breast cancer cells by conventional cytotoxic chemotherapy. Hum Pathol 2010;41:574-81.
Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E, et al
. An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 2011;104:1730-8.
Hashimoto K, Shimizu C, Tsuda H, Saji S, Osaki A, Shigekawa T, et al
. Immunohistochemical detection of breast cancer stem cells in hormone receptor-positive breast cancer and their role in response to endocrine therapy and clinical outcome. Oncology 2012;82:168-74.
Bernardi MA, Logullo AF, Pasini FS, Nonogaki S, Blumke C, Soares FA, et al
. Prognostic significance of CD24 and claudin-7 immunoexpression in ductal invasive breast cancer. Oncol Rep 2012;27:28-38.
Ahmed MA, Aleskandarany MA, Rakha EA, Moustafa RZ, Benhasouna A, Nolan C, et al
. A CD44−
phenotype is a poor prognostic marker in early invasive breast cancer. Breast Cancer Res Treat 2012;133:979-95.
Kapucuoğlu N, Bozkurt KK, Başpınar Ş, Koçer M, Eroğlu HE, Akdeniz R, et al
. The clinicopathological and prognostic significance of CD24, CD44, CD133, ALDH1 expressions in invasive ductal carcinoma of the breast: CD44/CD24 expression in breast cancer. Pathol Res Pract 2015;211:740-7.
Seo AN, Lee HJ, Kim EJ, Jang MH, Kim YJ, Kim JH, et al
. Expression of breast cancer stem cell markers as predictors of prognosis and response to trastuzumab in HER2-positive breast cancer. Br J Cancer 2016;114:1109-16.
Moon YW, An HJ, Koo JS, Kim GM, Han H, Park S, et al
. CD44/CD24 and aldehyde dehydrogenase 1 in estrogen receptor-positive early breast cancer treated with tamoxifen: CD24 positivity is a poor prognosticator. Oncotarget 2017;9:2622-30.
Rabinovich I, Sebastião APM, Lima RS, Urban CA, Junior ES, Anselmi KF, et al
. Cancer stem cell markers ALDH1 and CD44+/CD24- phenotype and their prognosis impact in invasive ductal carcinoma. Eur J Histochem 2018;62:2943.
Department of Pathology, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]