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MicroRNAs for diagnosis and treatment of breast cancer?

April 26, 2010

Breast cancer is a complex disease, involving a variety of changes in gene expression and structure.  Recent advances in molecular profiling technology have shed new light on the biology of breast cancer.  Scientists have recently discovered small ribonucleic acids (RNAs) known as microRNAs (miRNAs), which may be novel biomarkers and therapeutic targets for breast cancer. 

MiRNAs control gene expression by regulating protein synthesis.  MiRNAs are found to be either decreased or increased in the cells of several cancers including breast cancer (Esquela-Kersher and Slack 2006; Veeck and Esteller 2010; Friedman et al. 2009).  MiRNAs are thought to control cell growth, differentiation, and death by binding to messenger RNAs (mRNAs) and inhibiting protein production. 

As evidence grows that miRNAs are aberrantly expressed in cancer, they may be novel biomarkers used to diagnose patients and assess their risk.  MiRNAs may be more effective in defining precise subsets of breast cancer compared to gene expression profiling that currently identifies the five major breast cancer subtypes.  Using miRNA-based classification could significantly change how a patient is treated.  A patient with abnormal miRNA expressions could be characterized to have a more aggressive tumor and poorer prognosis leading to aggressive treatment.  Other patients without the abnormal expressions could avoid unnecessary treatment and treatment-related toxicities.   

More than half of the known miRNAs are located in cancer-associated genomic regions (Calin et al. 2004).  Chromosomal region 11q23-24 is most frequently deleted in breast tumors as well as in lung, ovarian, and cervical cancers.  MiR-125b is located at this chromosomal region and is decreased in breast cancer (Iorio et al. 2005; Lowery et al. 2008).  Another chromosomal region 17q23 is commonly amplified in breast cancer.  Located at this chromosomal region, miR-21 is increased in breast cancer (Iorio et al. 2005; Lowery et al. 2008).      

MiRNA expression has specific pathologic effects on breast cancer.  The loss of miRNA let-7 was related to progesterone receptor (PgR) status, lymph node metastasis, and high proliferation index in breast tumors (Veeck and Esteller 2010).  MiR-30 was associated with estrogen receptor (ER) and PgR status (Lowery et al. 2008).  MiR-213 and miR-203 were associated with tumor stage (Lowery et al. 2008).  In addition, unique sets of miRNAs were identified with HER2 status (Lowery et al. 2008).

MiRNAs may also have an important function in metastasis.  In breast cancers, miR-10b was decreased compared with normal breast tissue.  But in 50% of metastatic breast cancer, miR-10b expression was increased leading to breast cancer invasion and progression (Negrini and Calin 2008; Ma et al. 2007).  Investigators have found other miRNAs associated with metastasis.  MiR-335, miR-126, and miR-206 suppressed breast cancer metastasis and migration; these miRNAs were consistently decreased in metastatic breast cancers (Negrini and Calin 2009).  MiR-373 and miR-520C stimulated cancer cell migration and invasion, and cells that developed metastases had increases in these miRNAs (Negrini and Calin 2008).       

Most deaths from cancer are associated with metastasis.  Prevention or elimination of cancer progression could have a major impact on cancer mortality.  Targeted therapies that use miRNAs to stop metastasis may be an effective approach to treat breast cancer.   

But our understanding of molecular and cellular determinants of metastasis remains limited.  Only a handful of miRNAs have been carefully studied so far, and the diverse expression patterns of miRNAs need to be investigated.  

Unpredictable response and development of resistance to adjuvant therapy are major challenges of treating breast cancer.  Whether miRNAs will be the “magic bullet” of future treatments remains to be seen, but research in this area may provide useful insights into breast cancer and lead to significant steps for personalizing cancer care.