|BREAST CANCER SYMPOSIUM - REVIEW ARTICLE
|Year : 2014 | Volume
| Issue : 3 | Page : 247-250
CD44: A key player in breast cancer
MT Anand, S Kumar
School of Biotechnology, International Institute of Information Technology, Pune, India
|Date of Web Publication||10-Dec-2014|
School of Biotechnology, International Institute of Information Technology, Pune
Source of Support: None, Conflict of Interest: None
CD44 is a principal transmembrane hyluronate receptor, which acts as a hook between Extracellular Matrix and the cytoskeleton. CD44 is up regulated in breast cancer, which in turn helps in tumor progression and metastasis. There has been a lot of attention given to CD44 in recent years because of the discovery, CD44+/CD24- lineage marks breast cancer stem cells. Recent clinical and experimental findings show that CD44 is involved in the tumor associated proliferation, invasion, migration, and in many pathways involved in maintaining cancer cells which inturn are correlated with patient's survival. All these findings make CD44 as a potential target for breast cancer treatment. The methods of literature search for this article include Pubmed, BMC cancer and other printed journal article.
Keywords: Breast cancer, breast cancer stem cells, CD44, hyluronan
|How to cite this article:|
Anand M T, Kumar S. CD44: A key player in breast cancer. Indian J Cancer 2014;51:247-50
| » Introduction|| |
Breast cancer is the number one killer and most frequently occurring carcinoma worldwide in women.  Breast cancer is characterized by over expression of ERBB2, BCL2 and mutations involving in genes TP53, BRCA1, BRCA2 and in other tumor suppressor genes and also characterized by the presence of estrogen and progesterone receptors in cancerous cells.  The prediction of clinical outcome in patients with breast cancer is generally based on tumor stage (TNM), and the presence of metastasis to distant organs. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters.  In order to cure cancer it is, therefore necessary to identify these cells and target them. Muhammad Al-Hajj et al. isolated the cancer initiating cells based on the surface marker CD44 + CD24−/low Lineage− .  This tumorigenic subpopulation can be serially passaged: each time cells within this population generated new tumors containing additional CD44 + CD24−/low Lineage− tumorigenic cells as well as the phenotypically diverse mixed populations of non tumorigenic cells present in the initial tumor. CD44 is a cell adhesion molecule involved in binding of cells to hyluronic acid, whereas CD24 is a negative regulator of the chemokine receptor CXCR4, a molecule involved in breast cancer metastasis.  Since CD44 marks the Cancer Initiating Cells (CIC), it plays a vital role in maintaining cancer cells, their progression, proliferation and metastasis.
This review briefs the findings in recent years about the role of CD44 in breast cancer behaviour, its use in disease prognosis, and as a potential target for therapeutic agents.
CD44 as a marker for breast cancer stem cells (BCSC)
There has been a postulate that virtually all cancers are clonal and represents a progeny of a single cell. But, what is not known is which cells within the tumor possess tumor-initiating cell (T-IC) function and has the ability of maintaining tumor growth. The paper by Al-Hajj et al. provides a huge leap in the identification of human breast cancer initiating cell (BrCa-IC) or Breast Cancer Stem Cells (BCSC).  In this study, Al-hajj et al. used four cell surface markers (adhesion molecules CD44 and CD24, a breast/ovarian cancer specific marker B38.1, and the epithelial specific antigen, ESA), whose expression is heterogeneous in breast cancer tissue, to sort out expressing and non-expressing fractions alone or in combination. All mice injected with CD44 + , B38.1− , or CD24−/low generated palpable tumors in 12 weeks, whereas none of the CD44− , B38.1− injections caused tumors, indicating the potential role of CD44 in maintaining the stemness of the BCSC. OCT4 (also known as POU5F1) transcription factor, known as a master pluripotency gene, found to have an intense expression in BCSC. ,, These cancer stem cells with high expression of OCT4 are associated with further disease progression, greater metastasis, and shorter cancer related survival rate.  CD44 is also associated with favourable prognostic criteria including lower Nottingham prognostic index, ER+, HER2-, luminal phenotype and found to be an independent predictor of good prognosis for the identification of BCSC. 
| » Role of CD44 variants in breast cancer|| |
CD44 is an 85-90 kDa integral transmembrane protein encoded by a single 20 exon gene located on the short arm of chromosome 11. In the standard form, known as CD44s, 10 of the 20 exons are transcribed. Multiple variant isoforms exist (CD44v1-10) which arise from alternative mRNA splicing of the remaining 10 exons.  This pre mRNA precursor splicing of specific gene is flexibly regulated, leading to the formation of different types of isoform, which may be associated with cell tumorigenesis and may even cause tumor metastasis. One such gene is SRP40, which is over expressed in breast cancer, correlating with the alternative splicing of CD44, forming variants such as CD44v2, v3, v5 and v6.  Antibody mediated investigation of the CD44 immuno-phenotype of normal, benign and malignant breast tissues show the qualitative and quantitative changes of CD44 expression.  Each isoform/variant plays a multifunctional role in breast cancer cells while the amount of CD44 does not correlate with age of patients or any physiological conditions as determined by double histochemical staining studies in study involving 60 cases of invasive ductal carcinoma of breast. 
Studies show that CD44v6 cells occur in higher number in ER+ carcinomas after neo adjuvant chemotherapy as well. They are also in higher number in quiescent carcinoma, than the cells with CD44v6- phenotype.  CD44v3 and v6 are highly expressed in breast carcinoma of invasive cribriform but it lacked expression of CD44v4 along with decreased expression of CD44s. , Over expression of CD44v6 results in rapid metastasis of tumorigenic breast cancer cells. 
CD44 can be detached from cell surface by proteolytic enzyme activities and can be found in blood serum. This amount is used as a diagnostic tool to differentiate between malignant and non-malignant tumors.  Histiocytoid Breast Carcinoma - a rare type of Breast cancer characterized by loosely cohesive tumor cells due to deceased expression of E-cadherin along with CD44 epithelial variants.  This expression of CD44 is found to correlate with the grade of cancer, with grade 3 tumor showing high expression. 
In a study involving serum of 82 patients, there was an elevated level of CD44v6 whereas overall CD44s and CD44v5 did not differ much. Also patients with CD44v6 concentration above 75% in their serum, showed an increased tumor size and increased lymph node metastasis.  Furthermore, the expression of CD44 variants in Breast cancer cells correlates with the overall patient survival rate. The overall survival rate of CD44v6− group of patients is significantly higher than that of CD44v6+ group. Simultaneously, the survival rate found to decrease with the stronger expression of CD44v6 and patients with CD44v7−v8+ have significantly lesser disease free and overall survival rates, compared with CD44v7−v8− patients. ,
| » CD44 in metastasis|| |
CD44 plays an important role in metastasis of breast cancer. Comparative mass spectrometry studies involving two cell lines shows an up regulation in CD44 in metastatic cell line as compared to non-metastatic cell line.  This invasiveness of breast cancer is brought by CD44 interacting with many proteins. Treating MDA MB 435s cells with TGF-beta resulted in co-localization of Membrane type-1 matrix metalloprotein (MT1-MMP) and CD44 in cell membrane and in an increased level of soluble CD44, which promotes metastasis.  On the other hand, cross linking of CD44 molecules leads to enhanced tumor invasion and metastasis simultaneously relocating MMP-9 and stimulating the expression of Lymphocyte Function associated Antigen-1 (LFA-1) and Very Late Antigen-4 (VLA-4). , This expression of LFA-1 and VLA-4 mediates integrin mediated adhesion of tumor cells to endothelial cells resulting in the tans-endothelial migration of tumor cells. But, the co- expression of MMP-9 along with CD44v4 is necessary in metastasis of tumor cells to lymph nodes, since sole expression of CD44v4 does not associate with node status.  These lymph node metastasised cells are found to have high expression of CD44v3. It is also found that the expression of standard form of CD44 (CD44s) promotes breast tumor invasion and metastasis to liver.  In another study, transformed cells have smaller complex of Sam-68, which has the ability to promote alternative splicing of CD44 which in turn results in cell migration.  Also up regulation of CD44 along with CXCR4, OPN and decrease in CDH1, CDH13, TIMP3 expression indicates the invasiveness of breast cancer and its affection to bone marrow metastasis, since CD44 expression promotes the Hyaluronan (HA) coat retention, which facilitates their initial arrest on Bone marrow endothelium. ,, In an in vitro study, Hepatocyte growth Factor (HGF) found to up-regulate CD44 expression mediated by Tyrosine Kinase pathway This HGF induced CD44 cell lines binds to Bone marrow derived endothelial cells, which subsequently results in trans-endothelial migration of tumor cells.  But there is no difference in the expression of CD44 between bone metastasised and primary breast cancer. 
The interaction of hyluronic acid with CD44 plays an important role in invasion, adhesion and motility of breast cancer. Binding of HA to CD44 activates Na (+) - H (+) Exchange activity which in turn promotes intracellular acidification and creates an acidic extracellular matrix environment. This leads to Hyal-2 mediated HA catabolism, HA metabolism and cysteine proteinase (Cathapsin B) activation resulting in Breast tumor cell invasion.  The interaction of HA with CD44v6 leads to only cell mobility whereas interaction with CD44s leads to invasion, adhesion and motility of breast cancer.  Also CD44v4 is a major E-selectin ligand promoting cell migration across endothelial monolayers.  In addition, proteins erbB2 and EGFR interact with CD44 causing aggressiveness in mammary carcinoma cells during metastasis. 
| » CD44 in pathways|| |
Many pathways are involved in maintenance of breast cancer stem cells (BCSC) showing high expression of CD44 with no/little expression of CD24. Hedgehog pathway is found to be the most active in this process. Downstream components of hedgehog pathway are highly active in BCSCs and suppression of Gli1-A Trans activator of Hh pathway, by Small Interferon RNA resulted in inhibition of proliferation of BCSC. , RT-PCR study of MDA-MB 453 cells shows an increase in the expression of beta-catenin and Notch1 genes, involved in Wnt and Notch pathways, which accounts for the maintenance and activity of BCSCs.  TGF-b pathways is specifically active in CD44+ cancer cells and its inhibition induced a more epithelial phenotype. 
| » CD44 in multiple drug resistance|| |
Multiple Drug Resistance (MDR) is a potent barrier to effective and long term therapy in cancer patients. These resistant cells express more CD44 mRNA and protein compared with other cells.  Interaction of CD44 with HA in tumor cells plays an important role in various aspects of malignancy and MDR. The expression of MDR proteins is crucial for the drug resistance properties of cancer cells and the CD44- HA interaction forms a major pavement for MDR expression in various possible ways. Interaction of CD44 with HA and Protein kinase epsilon, leads to the production of miRNA-21 and down regulation of tumor suppression protein PDCD4, resulting in an increase in Inhibitors of Apoptosis proteins, MDR1 protein.  Same interaction also leads to an up regulation of p300 and SIRT, ultimately resulting in expression of MDR1 and Bcl-X (L)- anti apoptic gene accounting for chemo resistance.  CD44-HA interactions on the other hand, causes the activation of Nanog, erbB2 signalling complex which in turn stimulates expression of MD transporter MDR1 and induces ankyrin binding to MDR1 resulting in efflux of chemotherapeutic drugs. ,
| » Targeting CD44|| |
CD44, since its involvement in tumor associated proliferation, invasion and migration, has been targeted for breast cancer therapies. Balic et al. has developed a novel protocol for identifying BCSC, optimized for multi-marker analysis by employing novel DyLight Technology, where three of the markers CD44, ALDH1 and cytokeratin are directly conjugated with DyLight dyes and later labelled secondary antibodies were used for visualization.  These cells with elevated expression of CD44 along with Bcl2 shows increased resistance to apoptosis.  Preventing the binding of Osteopointin (OPN) with CD44, inhibits adhesion, migration, invasion, local progress in vitro and metastasis in vivo by a fair amount while antibody mediated inhibition of CD44 in human breast cancer xenograft models shows reduction in tumor growth. , Cortactin is a novel transcriptional target of HA-CD44s signalling, in reducing Breast cancer invasiveness.  High Intensity Focused Ultrasound (HIFU) is used in the treatment of breast cancer, which causes an irreversible damage to breast cancer cells and blood vessels by significantly decreasing the expression of CD44v6 along with other proteins and a dramatic decrease in Telomerase activity.  Recently nanotechnology based multicolour photo-acoustic flow cytometry has been demonstrated to identify the CD44+ circulating tumor cells in mouse model of human breast cancer. 
Although in many studies of targeting CD44 shows promising results, there are some cases indicating its adverse effects. In a clinical trial involving the drug bivatuzumab mertansine (a combination of humanized monoclonal antibody bivatuzumab and a cytotoxic drug mertansine) which targets CD44v6 expressing cells in metastatic breast cancer, majority of the patients who received the drug showed many toxic effects such as National Cancer Institute Common Toxicity Criteria Grade 4 elevation of liver enzymes, National Cancer Institute Common Toxicity Criteria Grade 3 vomiting, and the most common toxicities were transient and mild skin disorders. 
| » Conclusion|| |
CD44 plays a potent role in every aspects of breast cancer involving cancer cells proliferation, progression and metastasis. Effective targeting of CD44 is vital for patient's survival. Many promising methods have been implemented to target CD44, such as usage of HA coated Drug Carriers (HADC) carrying drug doxorubicin (DOX) which shows high affinity and efficiency towards targeted drug delivery.  CD44 interaction with HA also plays an important role in cancer cell metastasis and drug resistance and the disruption of this interaction may lead to better tumor response to the conventional chemotherapeutic drugs. Pathways involving CD44 signalling can be targeted for the removal of BCSCs. Coming to bottom line, future studies will focus on targeted delivery towards CD44 cells, improved drug treatment, and pathophysiological roles of many other molecules that are involved in CD44 activity in maintaining the breast cancer cells, and effective breast cancer treatment.
| » Acknowledgments|| |
Summary of work done by the contributors: Primary tumours of breast, ovarian and ascites, and cancer cell line culture for identification and characterisation of cancer stem cells. TAR mice model development for the breast and ovarian cancer.
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