**3.2. Diagnostic approach and treatment of breast cancer**

The increasing use of modern adjuvant therapy (systemic) and diagnostic tools has resulted in enhanced treatment of early stage breast cancer patients, producing a substantial increase in the overall survival time from diagnosis. However, improvements in the treatment of relapsed metastatic cancer have been marginal at best. Therefore, there is an urgent demand to develop novel therapies to treat malignant and late stage breast cancer [9, 3]. At present the treatment options include surgery, chemotherapy, immunotherapy, hormonal supplements and radiotherapy [6]. Targeted hormonal therapy is available for patients with breast cancers that have been shown to aberrantly express an excess of receptors for hormones. Studies indicate that hormone receptor type breast cancers have a more favorable prognosis than other types. Hormonal therapies are often prescribed following surgery as an adjuvant treatment. For example, tamoxifen prevents the interaction between hormones and their target receptors, while aromatase inhibitors decrease the levels of circulating hormones. Physicians have administered tamoxifen for more than three decades to treat hormone receptor-positive breast cancer (PR+ve, ER+ve or both). Tamoxifen acts as an estrogen receptor antagonist; it blocks the binding of estrogen with its endogenous receptors. Similarly, herceptin, a human anti-HER2 monoclonal antibody, acts by binding to the HER2 receptor thus preventing the generation of growth factors signals in breast cancer cells. Herceptin and tamoxifen can be given alone or together with chemotherapy drugs such as doxorubicin or paclitaxel and radiotherapy if required. However, the heterogeneity of breast cancers remains a fundamental barrier against the accurate molecular classification of the cancers and the implementation of individualized therapy. It is noteworthy that not all patients with hormone receptor overexpression (ER+ve and/or PR+ve) respond favorably to tamoxifen therapy and not all patients that overexpress HER2 respond to Herceptin indicating the presence of other unknown factors that influence the response to breast cancer treatment.

At present, no effective targeted treatment options are available for triple negative breast cancer (TNBC) patients [6]. The degree of genetic aberrations and the absence of HER2, PR and ER receptors render TNBC patients unresponsive to traditional hormonal therapy. TNBC is all too often resistant to the cancer chemotherapy drugs available at present including paclitaxel and epirubicin, which are platinum-based drugs [2]. The definitions of luminal A and luminal B cancers in the clinic have been set using arbitrary criteria, rather than taking gene expression levels into account. This is probably due to the substantial heterogeneity in ER+ve tumors, which can confound the selection of an appropriate treatment regimen. But the Ki-67 index can distinguish between luminal A and luminal B cancer types. Ki-67 is a protein that is used as a cellular marker for proliferation and may serve to identify a potential fifth molecular subtype, normal-like breast cancer, which is similar to luminal A but is less proliferative,

 thereby showing decreased Ki-67: (ER+ve /PR+ve /HER2−ve-/Ki67−ve). Luminal B cancer can also be further subdivided into two subgroups: (ER+ve /PR+ve /Her2−ve-/Ki-67+ve) and (ER+ve /PR+ve / Her2+ve /Ki-67+ve).

Nowadays, much research effort has focused on the further sub-classification of breast cancer types, based on gene expression and gene mutations including miRNA signatures. However, the prognostic value of this approach is still not clear [3, 6]. A better understanding of gene expression patterns and genetic mutations should help to determine predictive and prognostic markers and identify novel therapeutic targets that could induce the selective silencing of gene expression [6]. It is known that BRCA1 and BRCA2 genes are mutated in all types of breast cancer including TNBC.-The expression of PLK1 has been reported as a possibly important marker for TNBC; in addition TP53, GADPH, HRAS, PCNA, CCND1, BIRC5, MYBL2 and IGFBP6 have been reported as being significantly down-regulated or upregulated genes that are differentially expressed in TNBC cells compared to normal cells, while other research groups have reported the elevated expression of the AR and EGFR gene among TNBC patients [6].

During the last decade, the targeting of small molecular weight protein kinases and monoclonal antibodies against cell surface receptors has shown great promise in the ongoing struggle against cancer. Unfortunately, many of the key genes that cause cancer are still considered to be 'non-druggable', and as a consequence insufficient research has been applied to targeting them. Most tumors, due to their heterogeneity and their genetic instability are highly unlikely to present a single target that is found suitable for a long term treatment regimen [9]. RNAi has been shown to be able to rapidly and efficiently suppressing the expression of any gene in many cell types, thus highlighting the possibility of treating cancer by drug action on any gene that has been shown to induce cancer.
