Cancer cells develop mechanisms that allow them to resist the action of anti-cancer compounds. This can reduce the exposure of the diseased tissue and so have consequences for the efficacy of a compound. One such important mechanism is efflux transport by the BreastCancerResistance Protein (BCRP) . It is therefore important to know whether a novel drug is a substrate for BCRP.
Abstract: Adenine triphosphate (ATP)-binding cassette (ABC) transporter proteins, such as ABCB1/P-glycoprotein (P-gp) and ABCG2/breastcancerresistance protein (BCRP), transport various structurally unrelated compounds out of cells. ABCG2/BCRP is referred to as a “half- type” ABC transporter, functioning as a homodimer, and transports anticancer agents such as irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), gefitinib, imatinib, methotrexate, and mitoxantrone from cells. The expression of ABCG2/BCRP can confer a multidrug-resistant phenotype on cancer cells and affect drug absorption, distribution, metabolism, and excretion in normal tissues, thus modulating the in vivo efficacy of chemotherapeutic agents. Clarification of the substrate preferences and structural relationships of ABCG2/BCRP is essential for our understanding of the molecular mechanisms underlying its effects in vivo during chemotherapy. Its single-nucleotide polymorphisms are also involved in determining the efficacy of chemo- therapeutics, and those that reduce the functional activity of ABCG2/BCRP might be associated with unexpected adverse effects from normal doses of anticancer drugs that are ABCG2/BCRP substrates. Importantly, many recently developed molecular-targeted cancer drugs, such as the tyrosine kinase inhisbitors, imatinib mesylate, gefitinib, and others, can also interact with ABCG2/BCRP. Both functional single-nucleotide polymorphisms and inhibitory agents of ABCG2/BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of these molecu- lar cancer treatments, so the pharmacogenetics of ABCG2/BCRP is an important consideration in the application of molecular-targeted chemotherapies.
Accumulating evidence now suggest that human cancers including breast, lungs, cervical, leukaemia, among oth- ers are driven by a subset of cells with the capability of self-renewal ability to generate and differentiate into a functional mature progeny. These cells are known as can- cer stem cells and were first isolated from acute myeloid leukaemia by John Dick and colleagues . The cellular hierarchy and organization within the breast are struc- tured in a way that stem cells generate all progeny and terminally differentiated cells with specialized functions of milk production. In breastcancer, a subpopulation of cells that displayed stem cell properties was identi- fied and characterized by cell surface markers CD44 expression and are thus called “breastcancer stem cells” (BCSCs) . Subsequent to identification of BCSCs in primary mouse xenografts model, a small population of the cells have shown to be more invasive than the dif- ferentiated cells which comprise the tumour bulk. More evidence now suggest that these cells contribute to can- cer relapse following treatments . The relative resist- ance associated with BCSCs appears to be multifactorial ranging from decreased level of oxidants production and increased DNA repair efficiency that help maintain their stemness. Moreover, the preferential targeting of rapidly dividing cells by most chemotherapy enables the BCSCs in their quiescent non-cycling state to persist after ther- apy [64, 65]. Another molecular mechanism mediating breastcancerresistance to trastuzumab chemotherapy is inactivation of the tumour suppressor PTEN, which activate the downstream Akt molecule and bypass HER2 activation .
Drug resistance is an obstacle that impairs the success of cancer therapies. In some cases relapse occurs in ini- tially responsive patients after repeated cycles of chemo- therapy due to the acquisition of tumor resistance . Multiple mechanisms contribute to drug resistance, such as increased drug efflux, altered drug metabolism, sec- ondary mutations in drug targets, and the activation of downstream or parallel signal transduction pathways [11,12]. The critical mechanism of cell drug resistance involves the ABC (ATP-binding cassette) protein trans- porters which pump drug molecules out of cells, leading to reduced effective concentration within them . Well-known ABC transporters include the multidrug re- sistance (MDR) protein or P-glycoprotein (MDR1, P-gp, ABCB1); the multidrug resistance-associated proteins (MRP1, ABCC1); and the breastcancerresistance pro- teins (BCRP, ABCG2) [14,15].
ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breastcancerresistance protein (BCRP) are highly expressed in bronchial epithelium. This review aims to give new insights in the possible functions of ABC molecules in the lung in view of their expression in different cell types. Furthermore, their role in protection against noxious compounds, e.g. air pollutants and cigarette smoke components, will be discussed as well as the (mal)function in normal and pathological lung. Several pulmonary drugs are substrates for ABC transporters and therefore, the delivery of these drugs to the site of action may be highly dependent on the presence and activity of many ABC transporters in several cell types. Three ABC transporters are known to play an important role in lung functioning. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis, and mutations in ABCA1 and ABCA3 are responsible for respectively Tangier disease and fatal surfactant deficiency. The role of altered function of ABC transporters in highly prevalent pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) have hardly been investigated so far. We especially focused on polymorphisms, knock-out mice models and in vitro results of pulmonary research. Insight in the function of ABC transporters in the lung may open new ways to facilitate treatment of lung diseases.
PUFAs may predispose the cell to injury and could be attributed to an increased oxidative p o t e n t i a l ^ Al t h o u g h it is generally believed that anthracyclines, such as DOX, exert their cytotoxic effects by binding to DNA, several observations suggest that it may also have a direct effect on cell m e m b r a n e s ' E v i d e n c e indicates that DOX need not enter the cell in order to exert its cytotoxic e f f e c t . This was demonstrated by covalently attaching Adriamycin to large, insoluble polymeric beads which stopped the drug penetrating into the cytoplasm or nucleus o f the cell. This immobilised Adriamycin reduced the survival o f murine leukaemia cells, the polymeric beads being non-cytotoxic. Although all membrane binding sites o f this drug have not been identified, binding to spectrin'^' and cardiolipin has been i d e n t i f i e d T h i s latter substance is o f interest as an increased cardiolipin content in membranes appears to be a shared characteristic o f malignant cells and cardiac mitochondria leading to speculation that this is why anthracyclines cause damage to cardiac tissue'^^. Hence, an explanation for increased cellular sensitivity to DOX may be that incorporation o f large amounts o f EFA into the membrane alters the interaction between drug and a critical membrane ta r g e t'in c r e a s in g drug effect at the membrane level. The insertion o f DOX into the cells membrane would also increase membrane fluidity"* self potentiating the enhanced passive diffusion o f drug into the cell. Anthracyclines have the ability to trigger the formation o f free radicals. The drugs are reduced by enzymes to semiquinones which in turn reduce molecular oxygen to the superoxide ion'^^. DOX stimulated superoxide formation is both exo- and endo-cellular with both playing a role in the ability o f DOX to kill human cancer cells, including the MCF-7 cell line'^^. This combined oxidative potential o f the drug and the fatty acid may in part explain the increased cell death observed in cells treated with EFAs prior to cytotoxic drugs. This suggests that there is no modulation o f drug uptake in either drug sensitive or resistant cells due to EFAs treatment, and that the effect observed was due to additive toxicity'^"'. This would fit in with our results that at sub-lethal doses o f GLA no increase in drug uptake or modulation o f resistance was observed, except for IDA.
Having observed pathway differences, we aimed to identify the largest gene expression differences between MCF7 and MCF7-LTED cells exposed to YC-1. Thus, we defined a twofold or greater change in MCF7-LTED cells (between basal and YC-1 conditions), and a 1.5-fold or greater expression change in MCF7 cells. In this ana- lysis, we identified 19 and 8 genes, respectively, that were down- and upregulated in MCF7-LTED cells exposed to YC-1 (Figure 3A). Consistent with the binding of YC-1 to ERα, many of these perturbed genes corresponded to loci that are differentially regulated by ERα in endocrine therapy resistance. Analysis of ChIP data of responsive and nonresponsive breast tumors  revealed significant differential ERα binding at several of these loci, with 10 of 27 showing increased binding in the nonresponsive setting (Figure 3B). From among this set, VAV3 was further included in a 271-gene list associated with poor clinical outcome . Following on from these observations, we performed ERα ChIP assays using extracts of MCF7 and MCF7-LTED cells in basal (DMSO) or YC-1-exposed conditions. By this method, we found two VAV3 sites with significant binding of ERα relative to the nonspecific im- munoglobulin control (Figure 3C). In addition, both sites showed ERα sensitivity (that is, lower binding) with expos- ure to YC-1, and one site (binding site 1) had significantly
A study developed by Schneider and D’Orsi (2010) points out that illiterate women have risk of mortality from BC is 7.4 times higher than in women with higher education. As for those with incomplete primary education, the risk is 3.76 times grea- ter. Women with higher income and education, who have more knowledge, adhere more often to preventive practices. That research corroborates this fact, because the resistance is directly proportional to the few years of formal study, which suggests that the poor knowledge about cancer contributes in a unique way in the search for pre- ventive practices for cancer and perhaps other diseases .
to regulation of apoptosis. TRX has been shown to bind and inactivate apoptosis signal-regulating kinase 1 (ASK1), with the latter to be released upon oxidative stress . Apart from its cellular functions, TRX can be secreted as an autocrine growth factor by a yet unknown mechanism. It is then sti- mulating the proliferation of cells derived from a variety of solid tumors . In addition, the cytochrom P450 sub- type 1B1 (CYP1B1) converts 17b-estradiol (abbreviated as E2) into the carcinogenic 4-hydroxyestradiol (4-OHE2). A study conducted in ER-positive MCF-7 breastcancer cells suggested TRX to be involved in the constitutive expres- sion of CYP1B1 and the dioxin mediated induction of CYP1B1 . It may, thus, be a potent co-factor of mam- mary carcinogenesis at least in estradiol responsive tumours. Like other thiol-containing proteins, thioredoxin overexpression was suspected triggering chemotherapy resistance . Hence, TRX overexpression in several tumour derived cell lines is associated with resistance to
In recent years risk factors for BC have been identified, although the etiology of the disease is still not under- stood. Risk factors that contribute to the development of BC include age, ethnicity, reproduction, some kind of hormones, lifestyle, bone density, genetic factors  and family history . The majority of hereditary breast can- cer (HBC) susceptibility can be attributed to germline mutations of to BreastCancer 1 and BreastCancer 2 genes (BRCA1 and BRCA2), which are responsible for 30-40% of HBC. Clinically, the basis of HBC is estab- lished at an early age, family history, bilateral BC, male
3. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breastcancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31(31):3997-4013 doi 10.1200/JCO.2013.50.9984.
Given our current knowledge of the biology of activating mutations of ERBB2, single agent antibody-based treatment strategies may be of limited clinical relevance. In particular, truncated p95HER2 fragments naturally evade antibody binding due to the absence of the extracellular domain and binding of trastuzumab to ectodomain- or kinase domain-mutated ERBB2 forms presumably fails to prevent ligand-mediated ERBB3-ERBB2 signaling (Agus et al., 2002). Our in vitro data furthermore indi- cates that, whereas survival of Ba/F3 cells expressing mutants of G309 and S310 was effectively inhibited upon trastuzumab treat- ment, other ectodomain-mutants were less responsive (Greulich et al., 2012). Further in vivo investigation will be required to deter- mine response in a more physiological setting. Additionally, it would be of interest to evaluate whether pertuzumab is able to bind and impact survival of cancer cells expressing ectodomain- mutants. It remains unclear whether combinatorial treatment of trastuzumab and pertuzumab would be effective, given recent data obtained from ERBB2-positive metastatic breastcancer (Baselga et al., 2012).
The transferrin receptor (TfR) is exposed on the surface of proliferating cells (recent review in Daniels et al.) , and TfR is frequently used as the target in nanooncologic therapy. In the human body, however, there are millions of normal cells expressing very high amounts of TfR. The disease hemochromatosis is a strong and eloquent exam- ple of this. Hemochromatosis is a group of diseases char- acterized by abnormal storage of iron . The metal, which is toxic to cells in high amounts, is stored mainly in the skin, the heart, the pancreas, and the liver–organs where TfRs are abundant [195–197]. These organs are poisoned by the metal. The patient develops diabetes, and the skin is discolored brown. These two clinical fea- tures have given the disease the nickname “bronze-dia- betes”. The patient usually dies from either heart or liver insufficiency. The clinical picture of hemochromatosis indicates that if a NP is targeted to TfR on the membrane of a cancer cell, and injected intravenously, the NP can be hijacked by TfR expressed in normal organs. Thus the NP is more likely to end up in a normal organ than in a malignant tumor. Aiming at cancer cells with a single surface marker (such as TfR) results in aiming at a single population in a mixture of different cell populations that are constantly changing and moving.
Oncogenic events combined with a favourable environment are the two main factors in the oncological process. The tumour microenvironment is composed of a complex, interconnected network of protagonists, including soluble factors suh as cytokines, extracellular matrix components, interacting with fibroblasts, endothelial cells, immune cells and various specific cell types depending on the location of the cancer cells (e.g. pulmonary epithelium, osteoblasts). This diversity defines specific “niches” (e.g. vascular, immune, bone niches) involved in tumour growth and the metastatic process. These actors communicate together by direct intercellular communications and/or in an autocrine/paracrine/endocrine manner involving cytokines and growth factors. Among these glycoproteins, RANKL and its receptor RANK, members of the TNF and TNFR superfamilies, have stimulated the interest of the scientific community. RANK is frequently expressed by cancer cells in contrast to RANKL which is frequently detected in the tumour microenvironment and together they participate in every step in cancer development. Their activities are markedly regulated by OPG (a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor able to bind RANKL. The aim of the present review is to provide an overview of the functional implication of the RANK/RANKL system in cancer development, and to underline the most recent clinical studies.
Formalin-fixed, paraffin-embedded (FFPE) core biopsies were retrospectively collected from 52 patients harboring histologically confirmed HER2-positive breastcancer who underwent neoadjuvant treatment consisting of trastuzumab and chemotherapy at Vall d’Hebron University Hospital and Humanitas Clinical and Research Institute from 2005 to 2011. Paired post-chemotherapy specimens were also available for 12 of these samples. Ethical approval was obtained from the review boards at the Spanish and Italian Institutions. Tissues from 21 HER2-negative breastcancer patients who underwent neoadjuvant anthracycline- or taxane-based chemotherapy were also collected and used as controls. The patient characteristics are presented in Supplementary Table 1. HER2-overexpressing breastcancer patients were divided into a discovery (n = 22) and a validation (n = 30) cohort. Response to therapy was dichotomized as pCR (defined by the absence of a residual invasive tumor in the breast and axillary lymph nodes) or RD. Among the 52 HER2- positive patients, 28 patients achieved a pCR, whereas the other 24 cases had RD (Supplementary Table 1).
A meta-analysis of 31 studies previously demonstrated that ABCB1 (MDR1/P-glycoprotein) expression in tumors is associated with a poor response to chemotherapy [9–36]. Although the strategy to interfere with the transport activity of ABCB1 (MDR1/ P-glycoprotein) has not been applied successfully in a clinical setting, accumulated data obtained from both in vitro and clinical samples indicate that ABCB1 (MDR1/ P-glycoprotein) serves an important role in determining phenotype, including the susceptibility of breastcancer cells to anticancer agents [5, 6, 29, 36–38]. Ota et al.  reported an association between a single nucleotide polymorphism (538G>A) in ABCC11 and the risk of breastcancer in Japanese women. In addition, Yamada et al.  recently reported that ABCC11 was expressed significantly more frequently in aggressive subtypes and was associated with a poor prognosis in patients with breastcancer. These findings indicate a certain role of ABCC11 in the development and progression of breastcancer. It is intriguing that the expression of two ABC transporters with different substrate specificity was increased simultaneously by long-term exposure to eribulin in seven breastcancer cell lines, regardless of the receptor status of the cell lines. Eribulin binds to the vinca domain of tubulin; however, its antimitotic mechanism is distinct from that of other microtubule inhibitors such as vinca alkaloids and taxanes. Although the mechanisms underlying the transcriptional regulation of ABCC11 have not been elucidated, a common transcriptional regulatory mechanism might exist for up-regulation of the ABCB1 and ABCC11 genes induced by eribulin-mediated stress.
Introduction: We report a case of stage IV breastcancer terminating in an unusual picture of radiologically occult micronodular pseudo-cirrhosis. Contrast-enhanced computed tomography showed no evidence of metastatic breastcancer within the liver. Unlike the few previously reported cases of intrasinusoidal spread of breastcancer, our patient was palliated with a transjugular intrahepatic portosystemic shunt along with salvage chemohormonal therapy. In addition, our patient demonstrated proof of the principle of the dependence of capecitabine (Xeloda) efficacy on dose scheduling as predicted by laboratory studies based on Gompertzian tumor growth and the Norton-Simon hypothesis. Case presentation: We report the case of a 52-year-old Caucasian woman who developed radiological signs of portal hypertension without radiological evidence of hepatic metastasis five years after being diagnosed with metastatic breastcancer. She was receiving chemotherapy for stage IV breastcancer initially thought to be metastatic only to the bones. During salvage therapy with high-dose estradiol (Estradiol valerate), vinorelbine (Navelbine) and bevacizumab (Avastin), she suddenly developed signs of portal hypertension confirmed on computed tomography and by portal and systemic venous pressure measurements. Drug toxicity due to bevacizumab (Avastin) was initially and incorrectly entertained as a cause. The patient underwent palliative transjugular intrahepatic portosystemic shunt and
The important CSC-targeting principles highlighted by Reya et al.  provide the foundation upon which con- temporary CSC Theory has been built. Early CSC theory suggested that tumour heterogeneity could be broadly divided in to two cell types, namely CSCs and differenti- ated cells. In the intervening years it has become clear that heterogeneity in at least some, and perhaps many or all, malignancies is due to the presence of multiple CSC types arranged as hierarchies . There is clear evi- dence that the identification and targeting of a single CSC-type has potential as a clinical strategy. Perhaps the most striking example of this was described in ovarian cancer, where targeting of Notch signalling in ovCSCs resulted in platinum-based elimination of disease in an animal model of otherwise refractory disease . However, a large collection of similar studies has not been produced in other malignancies. In addition, there have been few successes in the clinic. We propose that one of the key factors behind this failure is the complex hierarchical organisation of CSCs, which complicates clinical targeting. Rather than looking for a ‘ needle in a haystack’ , which was challenging enough, it appears that we must now locate and target a specific, clinically- relevant needle in a collection of similar needles within the haystack. Complicating this further, it ap- pears that CSC hierarchies are altered by and adapt in response to our interventions, making them com- plex moving targets.
Among women, breastcancer is the most common form of cancer diagnosed with 1 in 8 expected to be diagnosed during their lifetime 1, 2 . Due to increased awareness, earlier detection, and improved targeted therapies, mortality rates are declining and more patients are surviving longer after diagnosis 4 . As a result, there is a growing population of breastcancer survivors dealing with lasting side effects of treatment. Such side effects include: fatigue, decreased aerobic capacity and muscle strength, increased weight gain, and an overall reduction in quality of life 5 . Exercise has widely been supported as an effective measure in mitigating these adverse effects. Additional studies have further explored modifications to exercise prescription components in relation to the FITT (Frequency, Intensity, Time, and Time) Principle in an effort to maximize the reduction of negative side effects 9-12 .
Abbreviations: ABCFS, Australian BreastCancer Family Study; ABCS, Amsterdam BreastCancer Study; BBCC, Bavarian BreastCancer Cases and Controls; BBCS, British BreastCancer Study; BIGGS, BreastCancer in Galway Genetic Study; BSUCH, BreastCancer Study of the University of Heidelberg; CGPS, Copenhagen General Population Study; ER, estrogen receptor; ESTHER, ESTHER BreastCancer Study; GC-HBOC, German Consortium for Hereditary Breast & Ovarian Cancer; GENICA, Gene Environment Interaction and BreastCancer in Germany; GESBC, Genetic Epidemiology Study of BreastCancer by Age 50; HABCS, Hannover BreastCancer Study; HEBCS, Helsinki BreastCancer Study; HER2, human epidermal growth factor receptor 2; HMBCS, Hannover-Minsk BreastCancer Study; HUBCS, Hannover-Ufa BreastCancer Study; KARBAC, Karolinska BreastCancer Study; KBCP, Kuopio BreastCancer Project; KConFab, Kathleen Cuningham Foundation Consortium for Research Into Familial BreastCancer; LMBC, Multidisciplinary Breast Centre; MCBCS, Mayo Clinic BreastCancer Study; MCCS, Melbourne Collaborative Cohort Study; NBCS, Norwegian BreastCancer Study; NC-BCFR, Northern California BreastCancer Family Registry; OFBCR, Ontario Familial BreastCancer Registry; ORIGO, Leiden University Medical Centre BreastCancer Study; PBCS, NCI Polish BreastCancer Study; PR, progesterone receptor; RBCS, Rotterdam BreastCancer Study; SASBAC, Singapore and Sweden BreastCancer Study; SBCS, Shefﬁeld BreastCancer Study; SEARCH, Study of Epidemiology and Risk factors in Cancer Heredity; SZBCS, IHCC- Szczecin BreastCancer Study; UCIBCS, UCI BreastCancer Study; UKBGS, UK Breakthrough Generations Study.