Recent studies indicate a correlation between high expression of the POZ-ZF transcription factor Kaiso, and the aggressiveness of the triple negative breast cancer (TNBC) subtype. However, little is known about the biological roles of Kaiso in TNBC tumorigenesis and metastasis, which laid the foundation for this thesis. To elucidate Kaiso’s role in TNBC, we generated stable Kaiso depletion in two well-established TNBC cell lines – MDA-MB-231 and Hs578T – using RNA interference technology. Intriguingly, we observed that Kaiso depletion delayed the tumor onset of MDA-MB-231 but not Hs578T cells, and led to the reduced expression of the c-Myc oncoprotein in MDA-MB-231 but not Hs578T cells. We postulate that this reduction in c-Myc expression is partly responsible for the delayed tumor onset observed in MDA-MB-231 cells. Additionally, loss of Kaiso expression resulted in increased apoptosis of both MDA-MB-231 and Hs578T cells in vitro and in vivo, which was accompanied by reduced expression of the DNA repair protein BRCA1. Remarkably, bioinformatic analysis revealed that high Kaiso and BRCA1 mRNA expression correlates with the reduced survival rates of TNBC patients. Further characterization of the Kaiso-depleted cells revealed that loss of Kaiso expression strongly inhibited the metastatic abilities of MDA-MB-231 and Hs578T cells. Importantly, Kaiso depletion led to decreased TGFβ-receptor I and II (TGFβRI and II) expression that is essential for the activation of the TGFβ signaling cascade. Concomitantly, suppressing Kaiso led to reduced TGFβ signaling. As increased TGFβRI expression is independently associated with the poor prognostic outcome of breast tumors, and the TGFβ signaling pathway is highly involved in breast tumor metastasis, we hypothesize that Kaiso functions together with TGFβRI and the TGFβ signaling cascade to promote TNBC metastasis. An additional goal of this thesis was to investigate the role of Kaiso in the prevalence of TNBC in women of African ancestry (WAA) compared to Caucasian women – since increased Kaiso expression is implicated in the poor survival outcomes of breast cancer patients of African ancestry relative to their Caucasian counterparts. Using tissue microarray and immunohistochemical analyses, we revealed for the first time a high nuclear expression of Kaiso in TNBC tissues of WAA (Nigerian, Barbadian, African American) compared to TNBC tissues of Caucasian women. Collectively, these findings unveiled functional oncogenic roles for Kaiso in the tumorigenesis and metastasis of TNBC, and revealed a plausible link between high Kaiso expression, high African ancestry and the predisposition of young WAA to TNBC. / Thesis / Doctor of Philosophy (PhD)

Breast cancer is a complex heterogenous disease that consists of several different subtypes displaying distinct behaviors and responses to different treatments. It is the second leading cause of cancer death among women, and is the most commonly diagnosed cancer in women. Although recent developments have helped shed light into this disease, there is still much to investigate. One particular subtype of breast cancer, known as triple-negative breast cancer, remains the most aggressive, as this tumor type is of high histological grade and preferentially affects women with BRCA1 mutations and women who are younger than 40 years of age. Unlike other subtypes with better prognoses, triple-negative breast cancer still has no targeted therapy, and chemotherapy remains the primary systemic treatment. Recently, there has been an increase of interest in the SOXC family of high mobility group transcription factors and their roles in tumor development. Studies have revealed some of the effects that SOXC genes may have on various tumor types. However, further studies are still needed to elucidate the roles, functions, regulations, and mechanisms of these transcription factors. This study aims to focus on one particular gene in the SOXC family known as sex determining region Y-box 11. Recent studies have shown that sex determining region Y-box 11, also known as SOX11, is one of the factors required for maintaining the basal-like breast cancer phenotype and is also critical in regulating growth, migration, invasion, and expression of signature basal-like breast cancer genes. Emerging evidence also reveals that this transcription factor may have an impact on homologous recombination repair when DNA damage occurs, in triple-negative breast cancer. Using SOX11 overexpression and knockout cell models combined with basic science laboratory techniques and omics, the next generation of laboratory tools, this study seeks to explore the role and function of SOX11 in DNA damage in triple-negative breast cancer. The results of this study have confirmed the recent findings of the role of SOX11 in cell proliferation and growth in triple-negative breast cancer. It has also revealed that overexpression of SOX11 in triple-negative breast cancer cell lines leads to an increase in DNA damage, loss of BRCA1 function, and dysregulation in the cell cycle. High expression of SOX11 is also associated with worse prognostic outcomes in triple-negative breast cancer patients. Because overexpression of SOX11 resulted in a loss of BRCA1 function, there may be a potential role for SOX11 in inducing the BRCAness phenotype commonly seen in basal-like breast cancers. The results of this study strongly suggest that SOX11 is involved in defective DNA damage repair pathways. Further studies need to be conducted in order to evaluate SOX11 as an inducer of the BRCAness phenotype, which occurs when there is a homologous recombination repair defect and no germline BRCA1 mutation present. Because of this, SOX11 may also have the potential to act as a functional biomarker for therapies targeting DNA damage, as recent developments in identifying therapies that could potentially target homologous recombination repair defects have been promising.

The RAB guanosine triphosphates (RAS-related in brain) belong to the Ras superfamily of GTPases, and loss of RAB 25 expression has been reported in a number of breast cancer cases containing H-Ras point mutations, particularly triple negative breast cancers (TNBC), one of the most aggressive subtypes of breast cancer and associated with a poor prognosis. The mechanism involved in the progression of these tumors is poorly understood. In this study, we are trying to understand if loss of RAB25 expression in Human Mammary Epithelial Cell (HMEC) lines co-operates with H-Ras mutations and contributes to tumorigenesis. HMEC were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, catalytic subunit of the telomerase enzyme that permits the cells to exceed the Hayflick Limit and become immortal. We have found that with loss of RAB25 and over expression of mutant H-Ras61L, immortal HMEC undergo transformation. We have looked into the co-operativity between loss of Rab25 and H-Ras61L mutant by in-vitro studies to show their anchorage independent growth and increased ability to migrate. Furthermore, cells express low CD24, high CD44, and very low levels of Claudin indicating that cells acquire stem-like properties upon transformation. Loss of RAB25 and over-expression of H-ras61L resulted in increased expression of transcription markers Snail and Slug that drive these cells to lose E-cadherin and undergo Epithelial Mesenchymal Transition (EMT). This study shows that loss of RAB25 and over-expression of mutant H-Ras can transform HMEC and give rise to mesenchymal stem-like tumors. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker in the prognosis of Claudin-low type of TNBC.

Breast cancer is one of the most common malignancy diagnosed in women and is the primary cause of cancer-related deaths in women worldwide. It is a heterogeneous group of diseases that have a different response, prognosis, and clinical outcomes. Estrogen, progesterone and HER2 negative breast cancer, known as triple negative breast cancer (TNBC), does not respond to hormonal therapy. Basal-like breast cancer (BLBC) has shorter overall survival rate among other subtypes. Tumors sharing both TNBC and BLBC are considered less responsive to currently available treatment. Chemoresistance to treatment has been a challenge in cancer biology and force investigation toward developing new targeted therapies, which selectively target specific subtypes. Sphingolipid metabolites have an important physiological role in determining cell fate. Sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate (S1P), are implicated in cancer. S1P exerts its functions via extracellular and intracellular targets. S1P synthesized inside the cell is exported outside and binds to G-protein coupled receptors, the sphingosine-1-phosphate receptors 1-5 (S1PR1-5). Although the intracellular function is not well defined, its suggested intracellular S1P promotes cell apoptosis. The S1P pathway has received great attention recently due its function in cell survival and death. This effect was reported to be concentration dependent. In this research, I focused on S1P effect on nine TNBC/BLBC cell lines. I examined the in-vitro effects of S1P on apoptosis, proliferation, and cytotoxicity in triple negative/ basal-like breast cancer cell lines. Moreover, I studied the co-administration of S1P with currently used chemotherapeutic agents in these cell lines. Data show that S1P can selectively induce cell death in TNBC/BLBC cell lines at a specific concentration. In this research, I found that the mechanism of cell death following treatment with different S1P concentrations was mainly due to apoptosis. Results show that S1P leads to cell shrinkage, rounding and detachment in the nine TNBC/BLBC cell lines. S1P combination with doxorubicin and docetaxel at different concentrations shows no beneficial effect of the combination compared to the chemotherapeuitc agent alone. In some cell lines, the combination showed a protective effect. Further studies are required to determine the mechanism by which S1P induces cell apoptosis, inhibits cell growth, and demonstrates lack of responsiveness in combination studies.

Colon and breast cancers are amongst the leading causes of cancer deaths in the United States, mostly attributed to metastasis and resistance to therapy. Hence, there is a critical need to identify novel biomarkers for effective prognosis and to design targeted therapies to combat the metastatic diseases. Loss of heterozygosity (LOH) at chromosome 18q and inactivation of the target gene, SMAD4, corresponds to resistance to the common chemotherapeutic agent, 5-fluorouracil (5-FU), in colon cancer. Our examination of the therapeutic resistance phenomenon in SMAD4-negative colon cancer cells with the three common agents revealed significant resistance to both 5-FU and irinotecan but not to oxaliplatin. We also followed up with the earlier findings from our group, which suggested that SMAD4 might interact with metastasis-promoting factors to suppress metastatic progression and render sensitivity to chemotherapy. Co-immunoprecipitation and mass spectrometry analysis revealed that SMAD4 interacts with and inhibits RICTOR, a component of mTORC2 that activates oncogenic AKT via phosphorylation at Serine 473. Overexpression of SMAD4, depletion of RICTOR, or inhibition of AKT signaling restores sensitivity to irinotecan in SMAD4-negative colon cancer cells in vitro. Furthermore, as expected pharmacological inhibition of AKT sensitizes these cells to irinotecan in vivo. Interestingly, high RICTOR/AKT expression correlates with worse survival in colon cancer patients, suggesting them as novel prognostic biomarkers and therapeutic targets. On the other hand, triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer due to lack of effective targeted therapies. Using miRNA expression profiling of a model for epithelial-mesenchymal transition in TNBC, we found suppression of miR-4417 during the progression from non-malignant to malignant stage. Furthermore, localization of miR-4417 to chromosome 1p36, a region corresponding to high frequency of LOH in multiple cancers and low-level expression in TNBC patients associated with poor overall survival is consistent with its likely role as a tumor suppressor. Interestingly, we found that overexpression of miR-4417 is sufficient to inhibit migration and tumorigenecity of TNBC cells in vitro. Overall, our findings suggest miR-4417 exerts a tumor-suppressive effect and could serve as a novel prognostic biomarker and therapeutic tool against TNBC. / 2021-02-20T00:00:00Z

Les cancers du sein triple-négatif (TNBC) (RE-, RP-, HER2) représentent 15% des cas de cancer du sein. Les patientes atteintes de TNBC sont traitées uniquement par chimiothérapie. A l’heure actuelle, il n’existe aucune thérapie ciblée efficace. Malgré une chimiosensibilité initiale, les rechutes sont fréquentes. Ainsi de nouveaux traitements sont nécessaires pour soigner ces patientes. Dans le cancer du sein, l’aspartyl protéase cathepsine D (cath-D), un marqueur de mauvais pronostic, est surexprimée par les cellules cancéreuses et est hyper-secrétée dans le microenvironnement tumoral. La cath-D stimule la prolifération des cellules cancéreuses, la croissance invasive des fibroblastes, la croissance tumorale, l’angiogenèse tumorale et la formation des métastases. Différentes études ont mis en exergue le rôle oncogénique de la cath-D extracellulaire dans le cancer du sein, suggérant qu’elle serait une cible thérapeutique d’intérêt. Afin de neutraliser sélectivement la forme sécrétée de la cath-D, le laboratoire a généré des anticorps humains IgG1 dirigés contre la cath-D par un crible de phage display (International patent N° PCT/EP2016/061454).Les principaux objectifs de ma thèse ont été i) de valider la cath-D comme une cible extracellulaire d’intérêt pour les patientes atteintes de TNBC, ii) d’évaluer les effets thérapeutiques et iii) de caractériser les mécanismes d’action des anticorps humains anti-cath-D.Nous avons montré que des niveaux élevés d'ARNm de CTSD sont corrélés à une survie sans récidive plus courte. Par analyse protéomique et étude immunohistochimique anti-cath-D réalisée sur Tissue Micro-Array, nous avons observé que la cath-D extracellulaire est détectée dans le microenvironnement tumoral des TNBC contrairement au tissu mammaire normal. Nos résultats mettent ainsi en exergue que la cath-D serait un biomarqueur tumoral extracellulaire, suggérant que les patientes atteintes de TBNC pourraient bénéficier d’une thérapie par des anticorps anti-cath-D. Par des analyses de SPECT-CT (Single Photon Emission Computed Tomography) et de biodistribution, nous avons validé que les anticorps humains anti-cath-D, F1 et E2, s’accumulent dans les xénogreffes de la lignée TNBC MDA-MB-231 chez la souris athymique. Les anticorps F1 et E2 inhibent la croissance tumorale des xénogreffes MDA-MB-231 et améliorent la survie des souris athymiques. Notre meilleur anticorps anti-cath-D, F1, inhibe également la croissance tumorale de deux lignées de TNBC PDX (patient-tumor derived xenografts). Au niveau mécanistique, l’anticorps F1 module le microenvironnement immunitaire dans les tumeurs issues des xénogreffes MDA-MB-231. L’ensemble de nos résultats suggèrent qu’une immunothérapie avec des anticorps humains anti-cath-D pourrait être une nouvelle approche thérapeutique pour les patientes atteintes de TNBC. / Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases, and chemotherapy is the only available treatment. Thus identification of new therapeutic targets is required to improve TNBC outcome. In breast cancer, the aspartic protease cathepsin D (cath-D) is a marker of poor prognosis associated with metastatic risk. This protease is overexpressed by breast cancer cells and is abnormally hypersecreted into the tumor microenvironment. Cath-D affects both cancer and stromal cells in the breast tumor microenvironment by increasing the proliferation of breast cancer cells, fibroblast invasive outgrowth, tumor growth and angiogenesis, and metastasis formation. Many studies indicated that extracellular cath-D displays oncogenic activities, suggesting it could represent a novel therapeutic target in TNBC. In order to block its oncogenic actions, the laboratory generated human IgG1 antibodies against extracellular cath-D by phage display (International patent N° PCT/EP2016/061454). The aims of my PhD project was i) to validate the potential value of cath-D as a tumor-specific extracellular target in TNBC, ii) to evaluate the therapeutic activity, and iii) to characterize the mechanisms of action of these anti-cath-D human antibodies.We showed that elevated CTSD mRNA levels correlated with shorter recurrence-free survival. Using proteomics analysis and anti-cath-D immunohistochemistry performed on Tissue Micro-Array, we observed that extracellular cath-D was detected in the tumor microenvironment of TNBC, but not in matched normal breast stroma samples. Our results thus indicate that cath-D is a tumor cell-associated extracellular biomarker and strongly suggest that it could be a good candidate for antibody-based therapy in TNBC. We found that anti-cath-D human antibodies, F1 and E2, accumulated in TNBC MDA-MB-231 tumor xenografts in athymic mice by SPECT-CT (Single Photon Emission Computed Tomography) and biodistribution analysis. F1 and E2 antibodies inhibited tumor growth of MDA-MB-231 tumor xenografts and improved mice survival without apparent toxicity. F1, the best antibody candidate, inhibited tumor growth of two TNBC patient-derived xenografts (PDX). Mechanistically, F1 treatment modulates immune tumor microenvironment in the MDA-MB-231 tumor cell xenograft model. Together, our results indicate that antibody-based targeting of cath-D may have therapeutic efficacy for TNBC treatment.

acase@tulane.edu / Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) whereby cells adopt a motile and invasive phenotype through loss of epithelial markers, namely Cadherin 1/E-Cadherin (CDH1), and acquisition of mesenchymal markers, such as vimentin (VIM) and Cadherin 2/N-Cadherin (CDH2). While MAPK/ERK1/2 kinase inhibitors (MEKi) have shown promise as antitumor agents in the preclinical setting, application has had limited success clinically. Activation of compensatory signaling, potentially contributing to the emergence of drug resistance, has shifted the therapeutic strategy to combine MEK1/2 inhibitors with agents targeting oncoproteins (RAF) or parallel growth pathways (PI3K). Conventional MAPK family members have been well-characterized in modulation of cellular processes involved in tumor initiation and progression, yet the role of MEK5-ERK5 in cancer biology is not completely understood. Recent studies have highlighted the importance of the MEK5 pathway in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast. Furthermore, elevated levels of ERK5 expression and activity observed in breast carcinomas are linked to worse prognosis in TNBC patients. The purpose of this work is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide rationale for combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance. / 1 / Van Hoang

Triple-negative breast cancer (TNBC) accounts for 15% of all diagnosed breast cancers nationally and affects African-American women 3 times more likely than any other ethnic group. Locally, African-American women in the New Orleans area see higher incidence of TNBC cases versus African-American women from the rest of the state of Louisiana, which represents an area of heightened public health interest for the metropolitan area. TNBC is a highly metastatic disease, and targeted therapies such as tamoxifen and herceptin are ineffective due to the lack of estrogen receptor (ER) and HER2/neu target expression in TNBC tumors. Chemotherapy remains the only effective drug therapy in TNBC cases. Evaluating new classes of drugs for clinical use against TNBC as well as furthering our understanding of underlying regulatory mechanisms in TNBC is a priority. Pan-deacetylase inhibitors (DACi), like panobinostat, have shown promise in clinical trials as therapies in other cancers. Pre-clinical data of panobinostat treatment in TNBC cell lines published by this lab has been positive so far, exhibiting a reduction in TNBC metastatic potential. DACi can alter multiple signaling pathways and are known to restore dysregulated microRNA (miRNA) expression patterns (miRnome) in cancers. MiRNA are a relatively new class of non-protein coding regulatory biomolecules that exhibit a variety of cancer-related properties, many still unknown in TNBC. Pan-DACi treatment combined with miRnome analysis in TNBC cell lines can be used to identify previously unknown miRNA cancer-related properties in TNBC. The specific aim of this project consists of using DACi treatment on TNBC cell lines in conjunction with miRnome analysis to identify previously undescribed anti-cancer miRNAs and elucidate their cancer-related properties in TNBC while uncovering affected cancer pathways, detecting miRNA targets, and revealing affected downstream components. Initial miRNA expression analysis of MDA-MB-231 TNBC cells treated with panobinostat or trichostatin A versus controls produced a list of potential anti-cancer miRNA candidates for further study. Among them, investigations into miR-203 and miR-335 produced unclear results as these were theorized to have anti-metastatic properties in TNBC yet enhanced cancer properties in our models and assays. Overexpression of mir-215 (a tumor suppressor in other cancers) unexpectedly enhanced tumor growth five fold in SCID mice xenografted with lentivirally-transduced MDA-MB-231 breast cancer cells stably overexpressing miR-215 (231/215+). Further qPCR analysis of 231/215+ cells uncovered upregulation of the breast cancer-associated lncRNA, HOTAIR; the breast cancer-associated miRNA, miR-196a; as well as the entire HOXC cluster in which they reside. This represents a previously unidentified regulatory mechanism of the HOXC cluster in humans. Additionally, miR-200b overexpression in MDA-MB-231 cells induced a change in cell morphology to an epithelial-like phenotype, reduced migration by 50%, and re-expressed the epithelial marker CDH1. This demonstrates a partial reversal of epithelial-mesenchymal transition (EMT), which indicates a reduction in metastatic potential by miR-200b overexpression in MDA-MB-231 cells. Additionally, these cells exhibited increased estrogen receptor alpha and related signaling pathways while also being susceptible to reduced proliferation with the anti-estrogen drug fulvestrant at high doses. Using pan-DACi treatment of TNBC cells to analyze changes in the miRnome for unknown cancer-related miRNA candidates suitable for further investigation in TNBC, we identified miR-215 overexpression in MDA-MB-231 cells as an oncogenic event that enhances tumor growth, cell proliferation, and HOXC cluster transcription while miR-200b is an anti-metastatic miRNA that partially reverses EMT and reduces fulvestrant resistance through re-expression of estrogen receptor signaling. / acase@tulane.edu

<p>Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer. Although some TN breast cancers respond initially to neoadjuvant chemotherapy, the majority of patients die within three years of treatment due to recurrent tumor growth. Developing ex vivo models for TN breast cancer recurrence and defining responsible molecules will be crucial to developing effective combination therapies for TN breast cancer patients. We have developed an in vitro model of TN breast cancer dormancy/recurrence. Short-term exposure of tumor cells to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, resembling therapy resistance of recurrent tumors in patients. Furthermore, we identify a novel signaling axis [nuclear bFGF/DNA-dependent protein kinase (DNA-PK)] supported by chemotherapy-enriched dormant TN breast cancer cells. This signaling axis drives accelerated DNA repair in chemo-residual TN breast cancer cells. Targeting this axis with either with a bFGF shRNA or DNA-PK small molecule inhibitor blocks recurrent colony formation. Using the Oncomine gene expression database, we found that bFGF expression in tumor samples from TN breast cancer patients predicts five year tumor recurrence following neoadjuvant chemotherapy treatment. Finally, we demonstrate that recurrent tumor cells exhibit increased invasiveness, reflecting the aggressive behavior of recurrent tumors in patients. Collectively, these studies identify a novel signaling axis in TN breast cancer that likely contributes to tumor recurrence and provide molecular targets for developing future therapeutics against TN breast cancer.</p> / Dissertation

abstract: In the U.S., breast cancer (BC) incidences among African American (AA) and CA (CA) women are similar, yet AA women have a significantly higher mortality rate. In addition, AA women often present with tumors at a younger age, with a higher tumor grade/stage and are more likely to be diagnosed with the highly aggressive triple-negative breast cancer (TNBC) subtype. Even within the TNBC subtype, AA women have a worse clinical outcome compared to CA. Although multiple socio-economic and lifestyle factors may contribute to these observed health disparities, it is essential that the underlying biological differences between CA and AA TNBC are identified. In this study, gene expression profiling was performed on archived FFPE samples, obtained from CA and AA women diagnosed with early stage TNBC. Initial analysis revealed a pattern of differential expression in the AA cohort compared to CA. Further molecular characterization results showed that the AA cohort segregated into 3-TNBC molecular subtypes; Basal-like (BL2), Immunomodulatory (IM) and Mesenchymal (M). Gene expression analyses resulted in 190 differentially expressed genes between the AA and CA cohorts. Pathway enrichment analysis demonstrated that differentially expressed genes were over-represented in cytoskeletal remodeling, cell adhesion, tight junctions, and immune response in the AA TNBC -cohort. Furthermore, genes in the Wnt/β-catenin pathway were over-expressed. These results were validated using RT-qPCR on an independent cohort of FFPE samples from AA and CA women with early stage TNBC, and identified Caveolin-1 (CAV1) as being significantly expressed in the AA-TNBC cohort. Furthermore, CAV1 was shown to be highly expressed in a cell line panel of TNBC, in particular, those of the mesenchymal and basal-like molecular subtype. Finally, silencing of CAV1 expression by siRNA resulted in a significant decrease in proliferation in each of the TNBC cell lines. These observations suggest that CAV1 expression may contribute to the more aggressive phenotype observed in AA women diagnosed with TNBC. / Dissertation/Thesis / Doctoral Dissertation Molecular and Cellular Biology 2015