Conservative surgery of breast and axilla, total mastectomy with axillary lymph node dissection +/− reconstruction, evaluation of whether there is lymph node involvement or not (26).

If the patients have minimum risk and are node-negative: endocrine therapy with tamoxifen is added. If the patients have moderate risk and are node-negative: treatment with luteinizing hormone-releasing hormone (LHRH) antagonist + tamoxifen. If these patients do not respond to the treatment chemotherapy is initiated. If the patients are node-positive: treatment with chemotherapy + tamoxifen (26).

The treatment is determined according to the molecular classification, age, predictive and prognostic factors and can be first-line hormone therapy or chemotherapy according to the case, and chemotherapy as a last resort in both situations (26). Despite the advances, most clinical treatments for breast cancer including chemotherapy or hormone therapy are not very successful in eliminating meta-static cells; invasive cancer is highly lethal, in fact, patients in stage IV have a survival of 15–27 months despite the most aggressive treatment and the most effective drug use (27,28). Endocrine drugs are the safest and most effective treatment in the management of hormone-sensitive breast cancer, although unfortunately tumor cells sooner or later develop a resistance to endocrine manipulation, and this has been observed in 40% of patients in advanced stages who do not respond effectively to tamoxifen (27,29). This occurs because the heterogeneous population of metastatic cells generally follows a different clinical course (27) due to changes in some factors of the tumor environment (as energy metabolism) (30) or genetic or epigenetic alterations of the cancer cells (31).

The purpose of adjuvant and systemic therapies is to improve the disease-free survival and survival rate associated with breast cancer through local-only treatments (surgery and radiation). For many years the treatment recommendations for adjuvant therapies were based on the anatomical classification and pathological factors such as tumor size, tumor grade and lymph node status. With the development of immunohistochemistry and genomic profiling techniques, different subtypes have been classified based on various markers and more specific therapies have been developed with a greater number of clinical benefits (32). There are a large number of drugs approved by Food and Drug Administration (FDA) for breast cancer. The list contains generic or brand names, and also includes the combinations in which they are used such as lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2 (33).

Chemotherapeutic agents can be classified according to many factors, including the specific phase of toxicity or the mechanism of action (34).

Multidrug resistance (MDR) is the greatest obstacle in the systemic treatment of breast cancer; it renders the disease uncontrollable and causes high mortality (35–39). It is therefore of the utmost importance to find drugs that can control breast cancer and offer better results. MDR can be intrinsic, where a fault is generated in the first-line therapy, which indicates there are pre-existing factors that mediate resistance in the tumor cells, or acquired, where initially the cells were sensitive to the treatment but resistance developed later on (30,39,40). The latter is characterized as being a resistance parallel to several drugs with a diverse structure and function and which are made up of different cell factors and transduction signals (36). In addition, as tumors are heterogeneous, it is believed that drug resistance may originate as a positive selection of a sub-population of drug-resistant cells (39). Fig. 2 shows several possible mechanisms involved in drug resistance.

There are three classes of pharmacological agents used in hormone therapy to treat ER⁺ breast cancer (42): a) selective estrogen receptor modulators (SERMs) such as tamoxifen; b) estrogen synthesis inhibitors like anastrozole, letrozole and exemestane; c) selective estrogen receptor degraders (SERDs), such as fulvestrant.

Tamoxifen has been reported as being of significant benefit to hormone-sensitive patients. It reduces the risk of recurrence after 5 years by 41% and of mortality by 34% and for decades has been the most successful treatment for ER⁺ cancer (32,42).

Endocrine therapy is considered the standard hormone therapy for patients with endocrine-sensitive tumors as defined by the ER or PR expression (1,32); although the classification of breast cancer as endocrine-sensitive depends on the hormones or positive for the estrogen receptor is referred to particularly as ERα (19). Endocrine therapy is based on three different strategies, which include: i) ER blockade through the use of selective ER modulators (SERM) like tamoxifen; ii) reduction in estrogen levels through aromatase inhibitors (AIs); iii) induction of ER degradation by SERDs like fulvestrant (29,42). ER belongs to the superfamily of nuclear receptors (29). There are two different molecular forms for the ER described, ERα and ERβ, which are coded by different genes and their expression has a specific tissue distribution, and in some cases shared distribution (29,42). ER activation can interact or activate directly or indirectly various growth factors of receptor tyrosine kinases (RTK) like HER-2, the epidermal growth factor receptor (EGFR), and insulin-like growth factor 1 receptor (IGF1R), among others (42). ERα has been associated most with carcinogenesis, whereas the loss of ERβ expression has been involved in tumor progression (19,42). The blocking of the signaling mediated by ERα is the mechanistic model for all hormonal interventions used to treat this disease (19). ERα (−) breast cancer remains one of the most therapy-resistant diseases, because of that differential protein expression between ER (+) and ER (−) tissues has been investigated (22). ERα (−) cells express lower levels of: i) superoxide dismutase, ii) RalA binding protein, iii) galectin-1, among others and expressed higher levels of Rho GDP-dissociation inhibitor 1α. The collective role of the alterations of protein expression in ERα (−) cells may be to promote a more malignant phenotype than adjacent ERα (+) cells (22).

According to authors (29) various resistance mechanisms can be found in endocrine therapy.

Targeted therapy represents the greatest hope in the war against cancer and is a very important step in personalized medicine. To avoid the various toxic effects of some drugs, antibody-drug conjugates have been developed that can aim the treatment specifically at tumor cells. One of these antibodies is trastuzumab emtansine (T-DM1), which can block the extracellular part of the bond to the HER-2 receptor ligand, inhibiting the pathological signal of HER-2 overexpression inside the cell. Because the benefit in the clinical response rate and absolute survival is small, more effective drugs are needed that can be conjugated with T-DM1 (43). Despite an optimal local treatment, virtually all patients with invasive breast cancer have some risk of relapse. This risk varies according to several factors related to the disease, which is why all women with this type of cancer could obtain benefits from adjuvant therapy. However, all these treatments have indirect side effects and potential risks that must be considered when evaluating the need for systemic therapy (26). In fact the side effects from adjuvant chemotherapies can be fatal in 1% of patients (32) and ~90% of mortality in breast cancer is due to metastases resistant to adjuvant therapies (44). Some of the acute and chronic side effects associated with breast cancer treatment are cardiotoxicity, one of the most important (for treatment with anthracyclins, radiation therapy, etc.), reproductive dysfunction, pneumonitis, arm lymphedema, changes in the skin, and others (45,46). Some effects of endocrine therapy are documented mainly with the use of tamoxifen and include pulmonary embolism, deep vein thrombosis and endometrial cancer. The aromatase inhibitors have been associated with an increased risk of cardiovascular disease, high cholesterol and acceleration of bone tissue loss in post-menopausal women (47).

It is known now that cancer cell populations contain a subpopulation of self-renewing stem cells known as cancer stem cells (CSC). Unlike normal adult stem cells that remain constant in number, such cells can increase in number as tumors grow, and give rise to progeny that can be both locally invasive and colonize to distant sites known as one of the hallmarks of malignancy. Cancer begins in normal somatic cells with a mutation that is called initiation. If the mutated cell has a selective growth advantage over its normal neighbor cells due to enhanced proliferation or resistance to apoptosis, then a clone of cells carrying the same mutation will emerge. The microenvironment surrounding blood vessels is conducive to the highest rates of tumor-cell proliferation, but it can also serve as the local stem cell niche, a microenvironment formed by nerves, mesenchymal cells and molecules of extracellular matrix that regulate aspects of stem cell behavior. The insensitivity of cancer stem cells to chemotherapy and radiation treatment has suggested that anticancer drugs may not effectively inhibit such cells, thus targeting them will be important to eradicate tumors in an efficient way. The clinical relevance of targeting genes of such cells is supported by experimental and clinical studies.

It is necessary to take into account that the mesenchymal phenotype is associated with characteristics of CSC for the development of anti-CSC therapies in the future. Incorporating the concepts of CSCs and the EMT into the biology of cancer may dramatically change the paradigm of anticancer therapy. The overall goal of cancer therapy is to target only the cancer cells leaving the viable normal cells behind. Therefore CSC eradication seems possible. Thus targeting of CSCs by their specific cell surface markers seems a logical approach to target therapy than other targeting strategies would be like signaling pathways or extracellular. If we can identify different populations of cells that exhibit cell surface markers and identify them as stem cells it will be possible to evaluate the effectiveness of new targeting strategies on that population. If we can show that there are cells that have specific behaviors to decrease apoptosis and make them resistant, then we are one step further in finding treatment to destroy them. There is a critical need for more direct markers to reduce the tumor microenvironment or circulating CSC to assess the direct impact of those CSC targeted therapies.

Tumor initiating cells have been identified in a variety of cancers by sorting of subpopulations based on cell surface markers and transplantation into animal models. Human breast epithelial cells with stem cell properties have been previously characterized based on cell surface marker. These cells exist in a less differentiated state and can proliferate in suspension to form mammospheres (48). Studies highlight the need to develop new therapeutic strategies which can target cancer stem cells. Among the cell surface markers, CD44 is expressed mostly in basal-like cell lines whereas CD24 in luminal-like cell lines. Other putative markers including CD44⁺/CD24⁻/ Low, Her2, ALDH, CD133, ER, PR and α6-integrin etc. are also overexpressed and drive tumorigenesis in different breast cell lines (49–51). In breast cancer CD44⁺/CD24⁻/low cells were identified as candidate breast cancer stem cells based on xenotransplant assays in immunodeficient mice (49). They investigated the genome-wide gene expression profiles of these cells, called, CD44⁺ and more differentiated luminal epithelial CD44⁻/CD24⁺, called, CD24⁺. Specifically, CD44⁺ cells showed a more mesenchymal stem cell-like profile enriched for genes involved in cell motility, proliferation, and angiogenesis, whereas CD24⁺ cells highly expressed genes implicated in carbohydrate metabolism and RNA splicing. In general the prevalence of CD24⁺/ CD24⁻/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Authors (52) reported that circulating tumor cells and biomarker can be considered for personalized targeted treatments for metastatic breast cancer.

A functional classification of breast cancer has proposed two hypotheses based on either breast cancer heterogeneity that arise from distinct mammary stem/progenitor cells at various levels or as a result of a single mammary stem/progenitor cell being affected by various oncogenes which give rise to various types of cancer (4). This has enabled the distinction of different molecular subtypes in breast cancer (25), and their identification make it possible to select a specific treatment strategy and to better predict the prognosis (6). Approximately 70% of all breast cancers diagnosed in the USA are ER⁺ (22,36). Currently one of the major efforts in integrative genomics related to cancer research is The Cancer Genome Atlas (TCGA), in which the genotype, epigenome, transcriptome, proteome, morphology and clinical records of hundreds of patients are available for each type of cancer including breast cancer (53).

Advances in research related to the classification of cancer have opened up new doors in terms of treatment. In light of tumor drug resistance cells, new therapeutic approaches are needed that can improve prognosis. Since cancer is a prevalent cause of mortality in adults, basic research and clinical studies are required to analyze the risks and benefits of these alternative therapies, and their connection to drug resistance. Such approaches would be important to implement since some patients, while their survival increases, are exposed to other pathologies and risks such as chronic diseases, among which cancer is emphasized. It is thought that one of the ways to prevent or overcome endocrine resistance is the combination of different targets in the therapy that effectively block both ER and RTK-dependent signaling (42), among other molecular mechanisms.

Oxidative stress has an important role in tumor growth and in conjunction with inflammatory processes is directly related to cancer development, progression and metastasis (54). Antioxidants have been studied in patients with cancer in the first place as potential anticancer agents that could improve prognosis, and second as reducers of the oxidative damage caused by chemotherapy and radiation therapy (55). Despite their potential use in therapies and preventive applications, their effects have been controversial (54). In fact, it has been reported that some supplements with vitamin A or E could even increase mortality significantly reducing in turn the effect of the conventional therapy (54,55). Conversely, there has been a statistically significant association between the dietary supplement vitamin C and a reduction in the risk and total and specific mortality in patients with breast cancer (56).

Another substance is the curcumin mayor component of the spice turmeric (Curcuma longa) and for several decades has proven to be a powerful anti-inflammatory agent and to have a great therapeutic potential against several types of cancer, blocking the transformation, proliferation and invasion of tumor cells (57–59). Curcumin suppresses multiple signaling pathways (58), such as caspase activation, induction of cell death receptors, aggregation of Fas receptors, induction of p53, and p21 pathways (57), release of apoptosis-inducing factor (57,60), regulation of the cell cycle (58,61), inhibition of PI3K-AKT activation, mTOR inhibition, downregulation of androgen receptors (57), inhibition of AMP-activated protein kinase, inhibition of COX2 and LOX 5, inhibition of STAT3 activation (57), c-Jun kinase activation, induction of DNA fragmentation, depletion of intracellular Ca², mitochondrial activation, direct damage to the DNA, anti-apoptotic protein suppression, autophagy, antioxidant mechanisms, proteasome activation, NF-κβ inhibition, among others (58,61). Thus, many studies have focused on improving its clinical effectiveness by modifying its delivery system through nanotechnology (62,63).