Multidrug resistance refers to the simultaneous resistance to structurally and mechanistically unrelated cytotoxic drugs. Chronic administration of cytotoxic drugs to patients with metastatic breast cancer results in the development of multidrug resistance, thus rendering chemotherapy unsuccessful. One mechanism by which multidrug resistance is conferred is the decreased intracellular drug accumulation due to the upregulation of the ATP-binding cassette (ABC) transporters. Jadomycins are polyketide-derived natural products produced by the soil actinomycetes Streptomyces venezuelae, ISP 5230. Jadomycins exhibit anticancer, antibacterial and antifungal activities. Pilot work in our laboratory demonstrated that jadomycin B exhibited similar cytotoxic effects in drug-sensitive and drug-resistant cancer cells. We hypothesize that jadomycins are poor substrates of ABCB1, ABCC1 and ABCG2 efflux transporters, and consequently will exhibit higher intracellular accumulation, which results in improved cytotoxic efficacy over existing chemotherapeutics that are rapidly effluxed by ABC transporters. Using methyltetrazolium (MTT) cell viability assays, the cytotoxic efficacy of nine jadomycin analogues (DNV, L, B, SPhG, F, W, S, T and N) in drug-sensitive and drug-resistant MCF7 breast cancer cells was evaluated. Jadomycin B, L, S and T were found to be equally toxic to drug-sensitive and drug-resistant ABCB1, ABCC1 or ABCG2-overexpressing MCF7 breast cancer cells. The inhibition of ABCB1, ABCC1 or ABCG2 efflux transporters with verapamil, MK-571 or ko143, respectively, did not significantly augment the cytotoxic effects of jadomycin DNV, L, B and S in drug-resistant MCF7 cells, suggesting that these jadomycins are poor substrates of the targeted transporter. Furthermore, all nine jadomycin analogues did not increase the intracellular accumulation of ABCB1, ABCC1 or ABCG2 probe fluorescent substrates in HEK-293 cells, indicating that these jadomycins do not inhibit the efflux function of the transporters. We conclude that jadomycins B, L and S are effective agents in the eradication of resistant breast cancer cells grown in culture, and that the ability of specific jadomycins to retain cytotoxic efficacy in resistant cells stems from their limited interactions with ABCB1, ABCC1 or ABCG2 efflux transporters.

No description available.

This dissertation explores how language has evolved as metastatic breast cancer (MBC) has shifted from an imminent death sentence to a potentially chronic disease. War rhetoric, of which the survivor trope is a part, has been the primary mechanism by which healthcare defines the cancer experience. Using Celeste Condit's framework of rhetorical formations, I question if a new rhetoric of breast cancer is indeed emerging as new developments in medicine allow women with terminal disease to live longer. My data reveals that this new rhetorical formation, of which metavivor rhetoric is the anchor point, contains its own key metaphors and rhetorical appeals. In metavivor rhetoric, the focus becomes living with cancer, in which simply existing through a sense of homeostasis develops as the central part of the rhetoric. In this homeostasis as the key part of metavivor rhetoric, a cure is not the focus, as it is in survivor rhetoric. I explore how this emerging rhetoric supersedes the war rhetoric that is deeply entrenched in medical discourse--especially breast cancer--for decades, and how metavivor rhetoric builds upon and repudiates the war rhetoric. Through my qualitative rhetorical analysis of a popular breast cancer message board for patients with metastatic disease, I coded 589 posts to see how women use language to discuss living with MBC, and Condit's concept of rhetorical formations allows me to argue more specifically for the changes I see in patient discourse. My analysis revealed that women living with MBC argue against war/survivor rhetoric and prefer metavivor rhetoric and its ancillary terms, allowing them to transition to an acceptance of their own mortality. I conclude that a new rhetorical formation has taken shape within MBC patient discourse, with implications for women's mortality as they live with a chronic disease, and as I look to the future of this research, my goal is to promote rhetorical changes that will help to enfranchise women with MBC into the broader breast cancer discourse in the United States. / Doctor of Philosophy / Metastatic breast cancer has become a disease that some women can live with for many years, as treatments have advanced for this specific type of cancer. As this disease has become a chronic condition for many women, the language that women use to discuss living with chronic cancer has also shifted. Using the framework of Celeste Condit's rhetorical formations, which encompasses uses of metaphors, topics, and values, among other rhetorical features, I examine how language has shifted from one of war and survivor rhetoric to that of metavivor rhetoric. In metavivor rhetoric, the focus becomes living with cancer, through a sense of homeostasis and of simply existing with cancer. Within homeostasis as the key part of metavivor rhetoric, a cure is not the focus, as it is in survivor rhetoric. By examining how women talk about living with cancer on a popular online breast cancer support group, I analyze the shifts that take place in their language and argue that women have moved from the dominant war and survivor rhetorical formation to one that is grounded in metavivor rhetoric and the idea of homeostasis. Within this evolution comes a transition to their own mortality as they come to better understand what it means to live with a chronic, yet ultimately, terminal, illness and an acknowledgment of the impact that their lives' perceived time has on these language choices.

Bakgrund: Bröstcancer är den vanligaste cancerdiagnos som kvinnor världen över drabbas av. Metastaserad bröstcancer (MBC) innebär att bröstcancern har bildat dottertumörer. Världshälsoorganisationen (WHO) definierar livskvalitet som individens uppfattning av sin livssituation i relation till rådande kultur och normer, och i förhållande till sina egna mål, förväntningar, värderingar och intressen. För att mäta livskvaliteten används mätinstrument i forma av enkäter och skalor som innehåller frågor som är indelade i olika områden som påverkar livskvaliteten. Enligt Erikssons omvårdnadsteori är hälso- och sjukvårdens huvudsakliga uppgift att lindra lidandet hos den lidande människan som lever med en sjukdom. Syfte: Syftet är att belysa vilka faktorer som påverkar livskvaliteten hos kvinnor skriv med metastaserad bröstcancer. Metod: En litteraturöversikt som baseras på 15 vetenskapliga artiklar.  Resultat: Kvinnor som har metastaserad bröstcancer har en lägre livskvalitet jämfört med kvinnor som har en annan form av bröstcancer. Faktorer som påverkar livskvaliteten kan beskrivas utifrån fyra kategorier; livskvalitet relaterat till typ av metastasdiagnos, livskvalitet relaterat till sjukdomstid, livskvalitet relaterat till behandling och livskvalitet relaterat till kvinnans rollfunktion med underkategorin livskvalitet relaterat till kvinnans ålder.  Konklusion: Resultatet visar en majoritet av kvinnorna upplever en lägre livskvalitet efter besked om sin MBC-diagnos. Den minskade livskvaliteten resulterar i ett livslidande och sjukdomslidande hos kvinnorna. Det är av stor av vikt att sjuksköterskan ser till den lidande kvinnan och beaktar hennes behov och upplevelser. Sjuksköterskan bör även arbeta familjecentrerat för att kunna ge den bästa vården för kvinnan och hennes familj. / Background: Breast cancer is the most common cancer diagnosis that women worldwide experience. Metastatic breast cancer (MBC) means that the breast cancer has formed daughter tumors. The World Health Organization (WHO) defines quality of life as the individual's perception of his or her life situation in relation to current culture and norms, and in relation to his or her own goals, expectations, values and interests. To measure the quality of life, measuring instruments in the form of questionnaires and scales, used that contain questions that are divided into different areas that affect the quality of life. According to Eriksson's nursing theory, the main task of health care is to alleviate the suffering of the suffering person who lives with a disease. Aim: The aim is to highlight which factors affect the quality of life of women with metastatic breast cancer. Method: A literature review based on 15 scientific articles. Result: Women who have metastatic breast cancer have a lower quality of life compared to women who have a different form of breast cancer. Factors that affect the quality of life can be described by four categories that are; quality of life related to type of metastasis diagnosis, quality of life related to disease time, quality of life related to treatment and quality of life related to the woman's role function with the subcategory quality of life related to the woman's age. Conclusion: Most of the women in the thesis work experience a lower quality of life after being informed of their MBC diagnosis. The diminished quality of life results in a life-long and disease-suffering of women. It is of great importance that the nurse looks to the suffering woman and considers her needs and experiences. The nurse should also work family-centered in order to provide the best care for the woman and her family.

Bakgrund: I Sverige drabbas årligen ca 7000 kvinnor av bröstcancer. 90 % av dessa överlever sin sjukdom tack vare goda behandlingsmöjligheter. Kvinnor med spridd bröstcancer lever allt längre tid med sin sjukdom. När bröstcancer sprider sig till andra organ än bröstet räknas den inte längre vara botbar. Behandling inriktar sig då till att vara lindrande eller palliativ. Bröstcancer är den vanligaste dödsorsaken för kvinnor i medelålder i Sverige. Syfte: Syftet med denna litteraturstudie är att belysa kvinnors upplevelse av att leva med obotlig bröstcancer. Metod: Åtta kvalitativa empiriska studier har sammanställts och analyserats med hjälp av beskrivande metasyntes. Artikelsökning utfördes i databaserna PubMed och CINAHL. Resultat: Resultatet från de valda artiklarna rörande kvinnors upplevelser av att leva med obotlig bröstcancer, kunde efter analys och konsensusdiskussioner sammanföras i fyra kategorier; Identitet, Relationer, Perspektiv samt Sorg och Förlust. Slutsats: Litteraturstudien visar att när kvinnor drabbas av obotlig bröstcancer förändras hela deras tillvaro drastiskt. Både livsperspektiv och roller hotas och leder till ångest och sorg. Kvinnorna upplever att det brister i bemötandet från vårdpersonal och behov av utvecklad kunskap och förståelse från sjuksköterskor är nödvändigt. Nyckelord: Metastaserad bröstcancer, Upplevelse, Relationer, Sorg, Omvårdnad / Background: In Sweden approximately 7000 women are diagnosed with breast cancer every year. 90% of these survive the disease because of good treatment possibilities. Women with cancer that has spread live longer with their disease. When breast cancer spreads to other organs it is no longer considered curable. Treatment then focuses on mitigation of pain and being palliative. Breast cancer is the most common cause of death for middle-aged women in Sweden.   Purpose: The purpose of this literature study is to shed light on womens experience of living with incurable breast cancer.   Method: Eight qualitative empirical studies have been collated and analyzed using descriptive metasynthesis. The article search has been carried out in the PubMed and CINAHL databases.   Result: The results from the chosen articles about women's experience of living with incurable breast cancer, could after a consensus discussion be brought into four categories; Identity, relations, perspective and finally sorrow and loss.   Conclusion: The literature study shows that when women are stricken with terminal breast cancer their lives change drastically. Both perspective on life and roles are threatened and lead to anxiety and sorrow. Women experience that the personal treatment they get from nursing staff is lacking, and that a higher level of knowledge and understanding in the nurses is necessary.   Keywords: Metastatic breast cancer, Experience, Relationship, Grief, Nursing

Docetaxel is a chemotherapeutic agent in the taxane group of drugs which is commonly used in the first line setting for metastatic hormone receptor negative breast cancer. We present a case of a 46 year old female who was diagnosed with de novo triple negative metastatic breast carcinoma, and has had an extended progression free survival (PFS) of almost 5 years on first line single agent treatment with Docetaxel. 46 year old female presented with a large left breast mass as well as axillary mass which revealed grade 3 invasive ductal carcinoma of breast on biopsy of both sites. Tumor was estrogen and progesterone receptor negative. Pathology showed discordance in HER2 testing between FISH and IHC, however on repeat testing, HER2 was confirmed to be negative. PET/CT scan for staging revealed large left sided pleural effusion and abnormal soft tissue in the lower anterior and posterior chest on the left concerning for pleural metastases. Patient underwent CT guided biopsy of left lower pleural space which was consistent with metastatic adenocarcinoma with breast primary. She was started on first line single agent chemotherapy with Docetaxel 100mg/m2 every 3 weeks. Tumor markers were non-contributory to assess disease response. Repeat systemic imaging in 3 months showed excellent partial response with decrease in size of breast mass, conglomerate axillary lymph nodes as well as pleural based metastatic foci. Patient had grade 1 neuropathy secondary to Docetaxel which was tolerable. Patient also had significant fatigue with warranted dose reduction by 20% after 6 months. She also demonstrated other adverse effects of Docetaxel such as nail dystrophy and mild blepharitis which were also tolerable. Patient showed good tolerance to chemotherapy, with intermittent treatment holidays. CT scans continued to demonstrate good response with stable size of breast and lung masses. After two years of stable disease and fair tolerance (after completing 34 cycles), chemo regimen was changed to every 4 weeks per patient’s wish. She was also started on Gabapentin for chemotherapy related neuropathy. At the end of 4 years, patient had completed 55 cycles of agent Docetaxel, maintaining ECOG of 1, with grade 2 neuropathy controlled with gabapentin. Patient is currently 56 months out from her initial diagnosis of metastatic triple negative breast cancer and follow-up scans continue to show stable disease. She has developed profound fatigue after several months of treatment. Patient has also faced challenges with fluid retention secondary to Docetaxel. Although her performance status remains fair, patient is contemplating changing frequency of chemotherapy to every 5 or every 6 weeks. Triple negative breast cancer is an aggressive disease with limited options of treatment with chemotherapy agents and no role for endocrine therapy or HER2 targeted treatment options. Docetaxel has shown to have median survival ranging between 10.1 to 14.7 months depending on the dose. Our patient has so far shown extended PFS of 56 months, with single agent Docetaxel in first line setting which surpasses current national averages.

<p>Breast cancer is the most frequently diagnosed malignancy and the second most lethal cancer in women. Metastasis in breast cancer is invariably responsible for patient death and is comprised of many steps, of which proliferation in vital organs is responsible for morbidity and mortality due to vital organ failure. Patients with the metastatic disease are limited to chemotherapy, which non-specifically targets proliferating cells. Despite it being initially effective, chemotherapy is associated with high toxicity and many patients develop resistance. Thus, there is an urgent need to characterize the biology of metastatic breast cancer to develop targeted therapies for the late-stage disease.</p> <p>EGFR is a member of the ErbB family of receptor tyrosine kinases, which have particular relevance in breast tumorigenesis. Clinical studies show that high expression levels of EGFR in the primary mammary tumors correlate with poor prognosis and decreased survival of breast cancer patients due to metastasis. Patient data is supported by experimental and pre-clinical studies, which describe various signaling pathways that mediate the oncogenic effects of EGFR, such as the MAPK, STAT3, and PI3K pathways. Despite these well-documented roles of EGFR, clinical trials evaluating EGFR inhibitors (EGFRi) in metastatic breast cancer have been unanimously unsuccessful in improving patient prognosis, and the mechanisms that contribute to this intrinsic resistance are unknown.</p> <p>To characterize the signaling events that govern EGFR behavior in metastatic breast cancer resistant to EGFRi, we utilized multiple pre-clinical breast cancer progression series and patient-derived cells that display the intrinsic resistance phenomenon. In these models, EGFR functions as a pro-apoptotic molecule whose ligand-mediated activation results in growth inhibition and/or apoptosis of metastatic breast cancer cells. Here we show that in the later stages of metastasis, increased nuclear translocation of EGFR leads to increased physical access to STAT1 and STAT3 molecules residing in the nucleus. Indeed, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1/3 phosphorylation. Additionally, specific inhibition of nuclear EGFR function using the EGFR kinase inhibitor gefitinib linked to a nuclear localization signal (NLS-gefitinib) prevents EGF-induced STAT1/3 phosphorylation. Altogether, these findings implicate nuclear localization of EGFR in downstream STAT1/3 signaling in metastatic breast cancer.</p> <p>Subsequently, we examined the involvement of nuclearly-activated STAT1/3 signaling in the apoptotic function of EGFR. NLS-gefitinib treatment or genetic/pharmacologic inhibition of STAT1/3 efficiently blocks EGF-induced apoptosis in metastatic breast cancer cells resistant to EGFRi. These findings were utilized therapeutically by activating EGFR with EGF treatment while simultaneously blocking the downstream proliferative MAPK:ERK1/2 pathway using the MEK1/2 inhibitor trametinib. EGF + trametinib combination preserved STAT1 signaling while effectively blocking the MAPK pathway, thus potentiating EGF-mediated apoptosis in metastatic breast cancer cells. Importantly, combined administration of trametinib and EGF resulted in STAT1-mediated apoptosis of primary mammary tumor cells, which respond to EGF in a proliferative fashion. These data provide a novel approach of targeting metastatic breast cancer by biasing EGFR signaling towards nuclear activation of STAT1/3 signaling resulting in apoptosis.</p> Our studies herein also examined the role of STAT3 in primary mammary tumor cells overexpressing EGFR. Depletion of STAT3 expression normalized the transformed phenotype of these cells <i>in vitro</i> and resulted in smaller mammary tumors <i>in vivo</i>. These results implicate STAT3 in EGFR-driven breast tumorigenesis localized to the mammary tissues. Further, systemic dissemination of breast cancer is associated with activation of the JAK1/2:STAT3 signaling axis. Despite the involvement of STAT3 in EGFR-mediated oncogenesis in the primary tumor setting, targeting JAK1/2:STAT signaling with the JAK1/2 inhibitor ruxolitinib proved ineffective in inhibiting the growth and invasion of metastatic cells derived from these primary tumors. These results are in agreement with the role of STAT1/3 in driving the pro-apoptotic function of EGFR in metastatic breast cancer cells. Altogether, these investigations provide a plausible explanation for the inability of JAK1/2 inhibitors to effectively target metastatic breast cancer in clinical and experimental investigations. Further, these findings indicate that the development of therapeutics or molecular tools that efficiently activate STAT1/3 signaling in metastatic breast cancer may represent an important concept for eradicating tumors resistant to targeted therapies.

Breast cancer is the most common cancer in a woman with a five-year survival of patients with metastatic disease is estimated at 23%. Ado-trastuzumab emtansine (T-DM1) is a HER2-antibody drug conjugate currently approved for the treatment of HER2-positive pre-treated metastatic breast cancer (BC). We report a case of recurrent metastatic breast cancer with unusually lengthy progression-free survival (PFS) on T-DM1 chemotherapy. She was diagnosed with Triple Positive Stage IIIC multifocal invasive ductal carcinoma of the left breast. After completing neoadjuvant chemotherapy, she underwent a bilateral mastectomy. Final pathology showed partial response. Postoperatively, she received adjuvant chemotherapy and radiation therapy. She was started on Q21 days trastuzumab following completion of adjuvant chemotherapy. Systemic imaging showed liver lesions and biopsy confirmed recurrence. She was started on T-DM1, endocrine therapy with anastrozole was continued. She is currently status post 45 cycles. T-DM1 was approved for the treatment (single-agent) of HER2-positive, metastatic BC based on phase III data from the EMILIA and TH3RESA study. Median PFS in the T-DM1 arm was 9.6 months. Herein, we present a case of a woman with recurrent triple positive metastatic BC with a lengthy progression-free survival on T-DM1 chemotherapy.

Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast carcinoma after two prior chemotherapeutic regimens. We report a patient with extended progression-free survival (PFS) of more than 57 months with metastatic breast carcinoma treated with eribulin in the third-line setting. A 48-year-old lady was diagnosed with stage IIA (pT2N0M0), high grade, triple-negative, invasive ductal carcinoma (IDC) of the left breast on core needle biopsy. She underwent neoadjuvant chemotherapy with adriamycin, and cyclophosphamide followed by a negative sentinel lymph node (SLN) biopsy. Subsequent mastectomy and axillary lymph node dissection revealed a 2.5 cm, high grade, triple-negative IDC with three additional lymph nodes negative for metastatic carcinoma, consistent with the initial diagnosis. Eight months into the surveillance program, the patient developed a 2.8 cm right lower lobe (RLL) lung mass with standard uptake value (SUV) of 27 on positron emission tomography-computed tomography (PET/CT). Core needle biopsy of the lung lesion revealed sheets of poorly differentiated carcinoma, immunophenotypically compatible with the initial diagnosis of breast pathology. She then commenced single-agent paclitaxel in the 1st line metastatic setting with a significant decrease in RLL lung mass to less than 1 cm with an SUV of 1.7 noted. The patient developed progression after seven months and started 2nd line gemcitabine noting initial improvement and subsequent stable disease for a period of 12 months. Eventual progression of RLL lung nodule measuring 2.1 cm with SUV of 10 noted. Initiated 3rd line eribulin with a notable response on imaging studies within three months and with no evidence of disease (NED) on scans over the subsequent 57 months. Eribulin related mild neuropathy superimposed on previous paclitaxel associated grade 2 neuropathy required a 20% eribulin dose reduction. The patient is currently clinically and radiographically stable with plateaued serum tumor markers. Our patient has shown excellent response and tolerance to eribulin with PFS of over 57 months (nineteen times the norm) which is rare.

Cancer is one of the leading causes of death in the world. For women in the U.S. and the European countries, breast cancer is the most common type and it continuously threatens the lives of the patients and causes huge economic losses. Chemotherapy and endocrine therapy are the common treatments for recurrence prevention and metastatic cancer symptom palliation. However, the uses of these therapies are meanwhile largely limited because their toxic side effects and non-specificity usually lead to low quality lives of the patients. Low aqueous solubility, multi-drug resistance, degradation of drug, limited intra-tumor diffusion and etc. are other limitations of conventional chemotherapies and endocrine therapies. Nanoparticle based drug carriers were extensively studied for therapeutic drug delivery. Many carriers could be loaded with high dose of hydrophobic and hydrophilic drugs, protect the drug from the surrounding in vivo environment during the transportation, specifically target and enter the tumor cells and slowly release the drug thereafter. Advanced nanoparticle drug carriers are studied driven by the need of a more efficient drug delivery. The 3rd generation of nanoparticle based drug carriers are recently developed. They usually consist of more than one type of nanoparticles. Different part of the particle has more specialized functions. Therefore, by carefully selecting from the conventional nanoparticle carriers, a 3rd generation particle could have the properties such as high loading capacity of multiple drugs, prolonged half-life in circulation, higher tendency of accumulating at the tumor site, improved specificity to the tumor cells, higher cell uptake rate and accurately triggered controlled release, and combination of the above-mentioned properties. In our study, a paclitaxel loaded nanoparticle supported immunoliposome was assembled for metastatic breast cancer drug delivery. Functionalized single walled carbon nanohorn or poly(lactic-co-glycolic acid) was encapsulated in the polyethylene glycol (PEG) coated liposome for high drug loading and controlled release. Anti-Her2 antibody or Herceptin® was grafted onto the surface of the liposome for a higher affinity to the Her2 overexpressing breast cancer cells. Firstly, the conjugation of protein to the surface of liposome and PEGylated liposomes were investigated. Proteins with or without membrane binding domain were conjugated to liposome and PEGylated liposomes through covalent and non-covalent binding for comparison. A modified enzyme-linked immune sorbent assay was developed for surface grafted protein quantification. Secondly, the encapsulation of solid nanoparticle into PEGylated immunoliposome was investigated. Results showed a new structure of solid nanoparticle in PEGylated immunoliposome at a 1:1 ratio was formed during the repeated freeze-thawing process. Supported immunoliposomes with high homogeneity in size and structure were purified by sucrose density gradient centrifugation. Thirdly, the drug loading, triggered release, cell binding, cell uptake and cell toxicities of the supported immunoliposome were studied. Release results showed a minimum drug leakage in serum at body temperature from the particle. The release was initiated with a minor burst trigged by low pH inside the tumor cell and followed with a long term linear pattern. Cell assay results showed the highest binding affinity of the antibody or Herceptin® grafted nanoparticles to Her2 overexpressing cell lines and a lysosomal intracellular distribution of the endocytosised particles. In the final study, a fabrication process for polymeric material nanoparticles was established. The process was capable of providing accurate control of the particle size with significant high output rates, thus largely extends the scope of materials for supporting the immunoliposome. / Ph. D.