Basal-like Breast Cancer Metastasis Research Articles

PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation.

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.

CBX7 regulates metastasis of basal-like breast cancer through Twist1/EphA2 pathway

BackgroundBasal-like breast cancer (BLBC) is an important subtype of breast cancer. Twist1 is a key transcription factor in BLBC metastasis, which serves a key role in tumorigenesis. The potential mechanism of Twist1 in BLBC remains to be elucidated. Here, we explored the role and molecular mechanism of Twist1 in BLBC. MethodsThe levels of CBX7, Twist1 and EphA2 in BLBC tissues and cells were determined by Western blot. ChIP and dual-luciferase reporter assays confirmed the interaction between CBX7, Twist1 and EphA2 promoter. The cellular functions were analyzed by CCK-8, colony formation, wound healing and Transwell assays. Expression of EMT related proteins was analyzed by Western blot. IHC measured the expression of CBX7, Twist1 and EphA2 in tumor tissues. ResultsCBX7 was down-regulated in BLBC tissues and cells, whereas Twist1 and EphA2 were up-regulated. Twist1 silencing inhibited the cell migration, invasion and cancer metastasis of BLBC through targeting EphA2 and regulating EphA2 expression. Additionally, CBX7 blocked the binding of Twist1 to EphA2 promoter and inhibited EphA2 expression and suppressed BLBC growth and metastasis via Twist1/EphA2 axis. ConclusionCBX7 suppresses BLBC growth and metastasis through Twist1/EphA2 pathway. Our study may provide evidence and new therapeutic targets for the comprehensive treatment of BLBC.

A two-pronged photodynamic nanodrug to prevent metastasis of basal-like breast cancer

A two-pronged concept combining photodynamic therapy (PDT) and epithelial-mesenchymal transition (EMT) blockade in a minimalist nanoplatform was proposed to combat basal-like breast cancer (BLBC) metastasis. Based on PDT-mediated tumor killing and epalrestat (Epa)-mediated EMT blockade, as-prepared Ce6/Epa nanoparticles prevented BLBC metastasis effectively in vivo, providing a very promising two-pronged strategy against BLBC metastasis.

FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-β and miR-182-5p.

The mesenchymal transcription factor forkhead box F2 (FOXF2) is a critical regulator of embryogenesis and tissue homeostasis. Our previous studies demonstrated that FOXF2 is ectopically expressed in basal-like breast cancer (BLBC) cells and that FOXF2 deficiency promotes the epithelial-mesenchymal transition and aggressiveness of BLBC cells. In this study, we found that FOXF2 controls transforming growth factor-beta (TGF-β)/SMAD signaling pathway activation through transrepression of TGF-β-coding genes in BLBC cells. FOXF2-deficient BLBC cells adopt a myofibroblast-/cancer-associated fibroblast (CAF)-like phenotype, and tend to metastasize to visceral organs by increasing autocrine TGF-β signaling and conferring aggressiveness to neighboring cells by increasing paracrine TGF-β signaling. In turn, TGF-β silences FOXF2 expression through upregulating miR-182-5p, a posttranscriptional regulator of FOXF2 and inducer of metastasis. In addition to mediating a reciprocal repression loop between FOXF2 and TGF-β through direct transrepression by SMAD3, miR-182-5p forms a reciprocal repression loop with FOXF2 that directly transrepresses MIR182 expression. Therefore, FOXF2 deficiency accelerates the visceral metastasis of BLBC through unrestricted increases in autocrine and paracrine TGF-β signaling, and miR-182-5p expression. Our findings provide novel mechanisms underlying the roles of TGF-β, miR-182-5p, and FOXF2 in accelerating BLBC dissemination and metastasis, and may facilitate the development of therapeutic strategies for aggressive BLBC.

Aurora B induces epithelial-mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis.

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.

MFAP5 promotes basal-like breast cancer progression by activating the EMT program

PurposeHuman basal-like breast cancer (BLBC) is an aggressive malignancy with poor prognosis. Since most current treatments are ineffective, there is an urgent need to identify therapeutic targets for BLBC. Microfibrillar-associated protein 5 (MFAP5) plays an important role in the integration of elastic microfibers and the regulation of endothelial cell behaviors. We previously demonstrated that MFAP5 was significantly overexpressed in BLBC tissues and associated with poor metastasis-free survival of patients with BLBC. However, the detailed role of MFAP5 in BLBC is unclear. Thereby, the current study aimed to investigate the underlying function of MFAP5 in BLBC.MethodFunctional analyses were conducted for the role of MFAP5 in BLBC in vitro and in vivo.ResultsOverexpression of MFAP5 resulted in a significant increase in the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) markers in BLBC in vitro and in vivo. In addition, other metastasis animal models by tail intravenous injection of BT20 cells further confirmed that MFAP5 overexpression promoted BLBC proliferation and BT20 cells metastasis. We found that the TGF-β or Notch inhibitor significantly reversed the tumorigenicity and metastasis of MFAP5-induced BLBC cells.ConclusionOur findings suggest that MFAP5 may promote EMT in BLBC metastasis via the TGF-β/Notch pathway.

Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1.

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive.Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients.Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients.Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells.

Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1.

Liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), has been identified as a tumor suppressor in many cancers including breast. Low LKB1 expression has been associated with poor prognosis of breast cancer patients, and we report here a significant association between loss of LKB1 expression and reduced patient survival specifically in the basal subtype of breast cancer. Owing to the aggressive nature of the basal subtype as evidenced by high incidences of metastasis, the purpose of this study was to determine if LKB1 expression could regulate the invasive and metastatic properties of this specific breast cancer subtype. Induction of LKB1 expression in basal-like breast cancer (BLBC)/triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, inhibited invasiveness in vitro and lung metastatic burden in an orthotopic xenograft model. Further analysis of BLBC cells overexpressing LKB1 by unbiased whole transcriptomics (RNA-sequencing) revealed striking regulation of metastasis-associated pathways, including cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT). In addition, LKB1 overexpression inhibited EMT-associated genes (CDH2, Vimentin, Twist) and induced the epithelial cell marker CDH1, indicating reversal of the EMT phenotype in the MDA-MB-231 cells. We further demonstrated marked inhibition of matrix metalloproteinase 1 expression and activity via regulation of c-Jun through inhibition of p38 signaling in LKB1-expressing cells. Taken together, these data support future development of LKB1 inducing therapeutics for the suppression of invasion and metastasis of BLBC.

Xenografts as models of clonal selection and acquired resistance to therapy.

Featured Article: Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, et al. Genome remodeling in a basal-like breast cancer metastasis and xenograft. Nature 2010; 464:999–1005.2 In our 2010 Nature article featured here, we described a next-generation sequencing-based whole-genome study to compare 4 related genomes from a single patient: a primary triple negative breast cancer, its counterpart xenograft [or “patient-derived xenograft” (PDX)], and a brain metastasis that occurred upon disease progression, all compared with the blood-derived normal DNA. This comparison identified a high degree of genomic similarity between all 3 tumor samples, and for the first time in a solid tissue malignancy we explored the alterations in genomic heterogeneity that occurred in the transitions from primary to metastatic disease, and from primary to PDX. Effectively, we demonstrated that somatic structural alterations remained constant across all 3 tumor genomes but that there were changes in clonality (inferred from the allele frequencies of point mutations) when comparing the primary to the metastasis and to the …

FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.

IntroductionOur previous clinical study demonstrated that the under-expression of FOXF2 is associated with early-onset metastasis and poor prognosis of patients with triple-negative breast cancer. In this study, we further characterized the role of FOXF2 in metastasis of basal-like breast cancer (BLBC) and underlying molecular mechanisms.MethodsRT-qPCR, immunoblot, immunofluorescence and immunohistochemistry were performed to assess the expression of genes and proteins in cell lines and tissues. A series of in vitro and in vivo assays was performed in the cells with RNAi-mediated knockdown or overexpression to elucidate the function and transcriptional regulatory role of FOXF2 in breast cancer.ResultsWe found that FOXF2 was specifically expressed in most basal-like breast cells. FOXF2 deficiency enhanced the metastatic ability of BLBC cells in vitro and in vivo. Additionally, FOXF2 deficiency induced the epithelial-mesenchymal transition (EMT) of basal-like breast cells. Furthermore, we identified that TWIST1 is a transcriptional target of FOXF2. TWIST1 was negatively regulated by FOXF2 and mediated the FOXF2-regulated EMT phenotype of basal-like breast cells and aggressive property of BLBC.ConclusionsFOXF2 is a novel EMT-suppressing transcription factor in BLBC. FOXF2 deficiency enhances metastatic ability of BLBC cells by activating the EMT program through upregulating the transcription of TWIST1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0531-1) contains supplementary material, which is available to authorized users.

Abstract SY45-02: Evaluation of targeted therapies in advanced breast cancer

Abstract SY45-02: Evaluation of targeted therapies in advanced breast cancer

Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer

Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here we identified that Snail interacted with Suv39H1, a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT, but also paves a way for the development of new treatment strategies against this disease.

Next-Generation Sequencing in Breast Cancer: Translational Science and Clinical Integration

PharmacogenomicsVol. 13, No. 6 EditorialNext-generation sequencing in breast cancer: translational science and clinical integrationMilan RadovichMilan RadovichDepartment of Surgery, Section of General Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. Search for more papers by this authorEmail the corresponding author at mradovic@iupui.eduPublished Online:19 Apr 2012https://doi.org/10.2217/pgs.12.18AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: breast cancerclinicalgenomic oncologygenomicsnext-generation sequencingtranscriptomicstranslationalReferences1 Lander ES, Linton LM, Birren B et al. Initial sequencing and analysis of the human genome. Nature409(6822),860–921 (2001).Crossref, Medline, CAS, Google Scholar2 Venter JC, Adams MD, Myers EW et al. The sequence of the human genome. 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Nature472(7341),90–94 (2011).Crossref, Medline, CAS, Google Scholar14 Futreal PA. Leveraging next generation sequencing in the study of breast cancer somatic genetics. Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 8–12 December 2010.Google Scholar15 Ellis MJ, Ding L, Shen D et al. Analysis of luminal-type breast cancer by massively parallel sequencing. Presented at: American Association for Cancer Research Annual Meeting. Orlando, FL, USA, 2–6 April 2011 (Abstract 87).Google Scholar16 Gustin JP, Cosgrove DP, Park BH. The PIK3CA gene as a mutated target for cancer therapy. Curr. Cancer Drug Targets8(8),733–740 (2008).Crossref, Medline, CAS, Google Scholar17 O’Shaughnessy J, Craig DW, Kiefer J et al. Next generation sequencing reveals co-activating events in the MAPK and PI3K/AKT pathways in metastatic triple negative breast cancers. Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 6–10 December 2011.Google Scholar18 Roychowdhury S, Iyer MK, Robinson DR et al. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci. Transl. Med.3(111),111ra121 (2011).Crossref, Medline, Google Scholar101 clinicaltrials.gov. www.clinicaltrials.govGoogle ScholarFiguresReferencesRelatedDetailsCited BySpecimens for Molecular Testing in Breast Cancer13 August 2015Breast TumorsBiomarker Testing for Breast, Lung, and Gastroesophageal Cancers at NCI Designated Cancer Centers12 September 2014 | JNCI: Journal of the National Cancer Institute, Vol. 106, No. 10Theranostic and Molecular Classification of Breast CancerArchives of Pathology & Laboratory Medicine, Vol. 138, No. 1Molecular and Cellular Heterogeneity in Breast CancerThe American Journal of Pathology, Vol. 183, No. 4Breast Cancer Heterogeneity in Primary and Metastatic Disease9 November 2012Breast cancer pharmacogenomics: where we are goingWilliam G Newman & Dave Flockhart19 April 2012 | Pharmacogenomics, Vol. 13, No. 6 Vol. 13, No. 6 Follow us on social media for the latest updates Metrics Downloaded 692 times History Published online 19 April 2012 Published in print April 2012 Information© Future Medicine LtdKeywordsbreast cancerclinicalgenomic oncologygenomicsnext-generation sequencingtranscriptomicstranslationalFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Luminal breast cancer metastasis is dependent on estrogen signaling

Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-β signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer.

MS1-3: Tumor Heterogeneity and Metastasis.

Abstract Massively parallel sequencing using Next Gen sequencing approaches have opened a new window into our understanding of the molecular architecture of breast cancer. A significant advantage of these technologies are that they are digital in nature because the measurement technology begins with single DNA molecules attached to a substrate. As a result, not only do these technologies provide an efficient means to identify somatic mutations, information is also provided on the frequency with which any given mutation is observed within the population of DNA molecules in the sample under analysis. The first and most striking feature of Next Gen analysis of breast cancer is the large numbers of somatic mutations that have been identified. Genome wide, thousands of mutations can be present in a single tumor. While this finding generates immense complexity from the perspective of defining biological drivers versus passengers, it does open up a new opportunity to study variations in mutation frequency. In a perfectly monoclonal tumor with a diploid genome and no contaminating normal cell DNA the mutation frequencies generated by digital sequencing will be 50% for a heterozygous mutation or 100% for homozygous mutations. Very few breast cancers subjected to whole genome sequencing exhibit this pattern, rather mutations occur with a wide variation of frequencies from the detection limit, around 5%, through to 100%. Furthermore mutation frequency clustering often occurs, a phenomenon best explained by the presence of a repertoire of mutations present in a founder clone that are present in all tumors, combined with additional less common mutations that represent a subdominant or minority population of cells that have arisen through additional clonal outgrowth. In a multiclonal model one of the most critical questions is “which clone determines the prognosis?”. One way to begin to answer this question is to sequence tumors before and after therapy and to compare primary tumors versus metastases. In our initial experience of a patient with a basal-like breast cancer in which a whole cancer genome was generated from her primary, her subsequent brain metastasis and a mouse xenograft generated from the breast primary, there was clear evidence of a shift in mutation frequency primary to metastasis, suggesting the brain metastasis arose from a minor sub-clone. The mutational profile of the xenograft more closely resembled the metastasis rather than the primary, suggesting the grafting process captured the metastatic clone (1). In this invited lecture we will present an extension of our sequencing experiences with further human progenitor-mouse xenograft comparisons, comparisons between human primaries and paired metastases and also examples of ER+ breast cancer genomes obtained before and after neoadjuvant endocrine therapy. In all these experiments multiclonality appears to be the rule rather than the exception. The clinical and biological implications of these findings will be discussed. 1. Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 2010;464(7291):999–1005. PMCID: 2872544. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS1-3.

Unraveling the complexity of basal-like breast cancer

Basal-like breast cancer (BLBC) is a form of breast cancer with generally poor prognosis that expresses basal cell markers and has an undifferentiated phenotype. The majority of BLBC is also classified as “triple-negative breast cancer” due to the lack of expression of the estrogen and progesterone receptors and the lack of overexpression of HER2. BLBC is the only major breast cancer subtype with no targeted therapies, and although ~20% of patients diagnosed with BLBC respond well to chemotherapy and are essentially cured, the remaining ~80% succumb to their disease in just a few years after diagnosis. Therefore, new molecular-based approaches to treating BLBC are urgently needed. Several recent studies, including our report in the July 2011 issue of The Journal of Clinical Investigation [1], have used large-scale, unbiased approaches to offer valuable insights into the details of complex aspects of BLBC. In our report, we explored how intratumor heterogeneity impacts BLBC. After screening 1,576 genes, we found that the JAK2/STAT3 pathway is preferentially required in CD44+CD24− breast cancer cells, which are most common in BLBC [2]. We identified a JAK2/STAT3 inhibitor, NVP-BSK805, that decreased basal-like breast tumor growth by eliminating this cell type, showing that targeting the JAK2/STAT3 pathway is a potential way to treat BLBC. Since we also found that basal-like breast tumors include CD24+ cells, which may also play a role in breast cancer progression [3], this would likely be most effective in combination with other cell type-specific drugs. Other researchers have also looked into the importance of intratumor heterogeneity in BLBC by taking into account the added complexity of cell plasticity. Using a high-throughput screen for inhibitors of cells that had undergone an epithelial-mesenchymal transition (EMT), Gupta et al. [4] discovered that the compound salinomycin inhibited basal-like breast tumor growth. Thus, therapies that target particular cellular phenotypes could be useful in treating BLBC. Corroborating this work, LOXL2 was recently found to be involved in EMT and BLBC metastasis [5]. Important BLBC discoveries have also come from looking at tumors as a whole rather than at specific cancer cell populations. Sun et al. [6] screened all known human kinases and phosphatases for anchorage-independent growth suppression and thereby elucidated a complicated intracellular network in triple-negative breast cancer. They found that PTPN12 normally suppresses HER2 and PDGFR-β and that inhibition of these together with lapatinib and sunitinib, respectively, greatly increased tumor growth inhibition. These results could be directly applicable to BLBC and suggest that drug combinations may often be necessary to kill the mixtures of cancer cells present in tumors. In another study at the whole-tumor level, published in the same issue of The Journal of Clinical Investigation as our report, Lehmann et al. [7] classified 587 triple-negative breast cancer cases into six subtypes using k-means clustering of gene expression data. Two of the identified subtypes were labeled as “basal-like” subtypes, and cell line models of them preferentially responded to cisplatin in culture and in mice. By scrutinizing intertumor heterogeneity, this work identified a potential treatment for BLBC, and it highlights the significance of personalizing breast cancer therapy. In summary, recent advances in BLBC are helping to unravel its complexity by improving our understanding of intratumor and intertumor heterogeneity, cell plasticity, and intracellular networks. Successful targeted treatment strategies for BLBC will likely be designed based on the potential targets and tumor biology details presented here as well as additional findings from the studies discussed and research inspired by them. These will likely include tumor-specific combinations of one or more drugs for multiple cell populations or states. Notably, such therapies may appear soon, as several of the inhibitors identified here, or related compounds, are already in clinical use or development.

Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

BackgroundTransforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-β antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody and LY2109761, a chemical inhibitor of TGF-β type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR).ResultsBoth 1D11 and LY2109761 effectively blocked TGF-β-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-β stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-β. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-β antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.ConclusionsIn aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.