Review Article | Published:

Emerging targeted agents in metastatic breast cancer

Nature Reviews Clinical Oncology volume 10, pages 191210 (2013) | Download Citation

Abstract

Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents.

Key points

  • Breast cancer cells are heterogeneous, with a multitude of molecular alterations supporting their malignant progression

  • Besides the epithelial compartment of the disease, the functional importance of the tumour microenvironment and of breast cancer stem cells has been recognized

  • A high number of emerging targeted agents against all the compartments of breast cancer are being developed in genotype-driven clinical trials

  • Rationally chosen combination targeted therapies hold promise for improving the clinical outcome of patients with metastatic breast cancer

  • Despite their refined mode of molecular action, targeted therapies are associated with diverse toxicities, which clinicians should be aware of and treat patients accordingly

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Trastuzumab—mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).

  2. 2.

    et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

  3. 3.

    & Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

  4. 4.

    & Breast-cancer stem cells-beyond semantics. Lancet Oncol. 13, e43–e48 (2012).

  5. 5.

    , , , & Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl. Med. 4, 127ps10 (2012).

  6. 6.

    et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

  7. 7.

    et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012).

  8. 8.

    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  9. 9.

    et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

  10. 10.

    et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353–360 (2012).

  11. 11.

    et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

  12. 12.

    & Unravelling the complexity of metastasis - molecular understanding and targeted therapies. Nat. Rev. Cancer 11, 735–748 (2011).

  13. 13.

    , & Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat. Rev. Cancer 12, 487–493 (2012).

  14. 14.

    et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

  15. 15.

    et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9, 16–32 (2012).

  16. 16.

    & PARP inhibitors in breast cancer: BRCA and beyond. Oncology (Williston Park) 25, 1014–1025 (2011).

  17. 17.

    , , & Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Disc. 8, 627–644 (2009).

  18. 18.

    et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10, 331S–3316S (2004).

  19. 19.

    et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J. Clin. Invest. 120, 2406–2413 (2010).

  20. 20.

    et al. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J. Biol. Chem. 284, 6361–6369 (2009).

  21. 21.

    , & Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition: a breakthrough in the management of luminal (ER+/HER2–) breast cancers? Curr. Opin. Oncol. 24, 623–634 (2012).

  22. 22.

    et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).

  23. 23.

    et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221–9230 (2008).

  24. 24.

    et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011).

  25. 25.

    et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

  26. 26.

    et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

  27. 27.

    et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036–1047 (2012).

  28. 28.

    US National Library of Medicine. ClinicalTrials.gov , (2012).

  29. 29.

    et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J. Clin. Oncol. 30, 2718–2724 (2012).

  30. 30.

    et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol. 27, 2630–2637 (2009).

  31. 31.

    et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).

  32. 32.

    et al. BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study [abstract]. Cancer Res. 72 (Suppl. 1), CT-01 (2012).

  33. 33.

    et al. Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res. 70, 1164–1172 (2010).

  34. 34.

    , , , & Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc. Natl Acad. Sci. USA. 109, 2718–2723 (2012).

  35. 35.

    et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011).

  36. 36.

    The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).

  37. 37.

    et al. Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer. Cancer Res. 49, 7002–7009 (1989).

  38. 38.

    et al. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J. Clin. Oncol. 26, 4078–4085 (2008).

  39. 39.

    , & Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone. Br. J. Cancer 75, 251–257 (1997).

  40. 40.

    , , , & Synergistic proliferative action of insulin-like growth factor I and 17 β-estradiol in MCF-7S breast tumor cells. Exp. Cell Res. 273, 107–117 (2002).

  41. 41.

    et al. Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur. J. Cancer 29A, 2256–2264 (1993).

  42. 42.

    et al. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin. Cancer Res. 70, 1204–1214 (2010).

  43. 43.

    Insulin-like growth factor receptor inhibitors: baby or the bathwater? J. Natl Cancer Inst. 104, 975–981 (2012).

  44. 44.

    et al. A randomized, double-blind, placebo-controlled, phase 2 study of AMG 479 with exemestane (E) or fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) metastatic (M) or locally advanced (LA) breast bancer (BC) [abstract]. Cancer Res. 70 (Suppl. 2), S1–4 (2011).

  45. 45.

    et al. Phase I dose escalation study of the anti-insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin. Cancer Res. 13, 5834–5840 (2007).

  46. 46.

    et al. A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl. 15), a3008 (2010).

  47. 47.

    & Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129 (2010).

  48. 48.

    , , , & The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors. Proc. Natl Acad. Sci. USA 86, 5678–5682 (1989).

  49. 49.

    et al. FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res. 9, R23 (2007).

  50. 50.

    et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70, 2085–2094 (2010).

  51. 51.

    et al. Characterization of the recurrent 8p11–12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer. Cancer Res. 68, 7165–7175 (2008).

  52. 52.

    et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin. Cancer Res. 12, 6652–6662 (2006).

  53. 53.

    et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 29, 2013–2023 (2010).

  54. 54.

    et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

  55. 55.

    et al. Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer. Endocr. Relat. Cancer 15, 101–111 (2008).

  56. 56.

    et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57, 963–969 (1997).

  57. 57.

    et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 16, 159–178 (2005).

  58. 58.

    , , & Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005).

  59. 59.

    et al. Significant antitumor activity of E-3810, a novel FGFR and VEGFR inhibitor, in patients with FGFR1 amplified breast cancer [abstract 3190]. Ann. Oncol. 29 (Suppl. 9), ix116 (2012).

  60. 60.

    et al. A multicenter, open-label phase II trial of dovitinib, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, inFGFR1-amplified and nonamplified metastatic breast cancer (BC) [abstract]. J. Clin. Oncol. 29 (Suppl. 27), a289 (2011).

  61. 61.

    , , & Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).

  62. 62.

    , , , & Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol. Int. 51, 172–178 (2001).

  63. 63.

    et al. Overexpression of c-Met and of the transducers PI3K, FAK and JAK in breast carcinomas correlates with shorter survival and neoangiogenesis. Int. J. Oncol. 31, 49–58 (2007).

  64. 64.

    et al. Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. Hum. Pathol. 38, 830–841 (2007).

  65. 65.

    et al. Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proc. Natl Acad. Sci. USA 106, 12903–12908 (2009).

  66. 66.

    et al. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene .

  67. 67.

    et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. Eur. J. Cancer 46, 1679–1691 (2010).

  68. 68.

    , , , 3rd & Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 68, 1471–1477 (2008).

  69. 69.

    et al. Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells. Mol. Cancer Ther. 10, 518–530 (2011).

  70. 70.

    et al. Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions. Endocr. Relat. Cancer 13, 1085–1099 (2006).

  71. 71.

    et al. Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. PLoS ONE 6, e15313 (2011).

  72. 72.

    et al. Cabozantinib (XL184) in patients with metastatic breast cancer: results from a phase 2 randomized discontinuation trial [abstract]. Cancer Res. 71 (Suppl. 3), P1-17-10 (2012).

  73. 73.

    , , , & Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11, 558–572 (2011).

  74. 74.

    & Cyclin D1 in breast cancer pathogenesis. J. Clin. Oncol. 23, 4215–4224 (2005).

  75. 75.

    et al. Cyclin E and survival in patients with breast cancer. N. Engl. J. Med. 347, 1566–1575 (2002).

  76. 76.

    et al. Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients. Int. J. Cancer 119, 2539–2545 (2006).

  77. 77.

    et al. A novel interaction between HER2/neu and cyclin E in breast cancer. Oncogene 29, 3896–3907 (2010).

  78. 78.

    et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol. Cancer Ther. 11, 1488–1499 (2012).

  79. 79.

    et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl Acad. Sci. USA 108, 3761–3766 (2011).

  80. 80.

    et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (BC) [abstract]. Cancer Res. 72 (Suppl. 24), 1–6 (2012).

  81. 81.

    et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (BC) [abstract 100O]. Ann. Oncol. 23 (Suppl. 2), ii43–ii45 (2012).

  82. 82.

    et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J. Exp. Med. 209, 679–696 (2012).

  83. 83.

    , , , & Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development. Breast Cancer Res. 11, 209 (2009).

  84. 84.

    et al. Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients. Int. J. Cancer 89, 384–388 (2000).

  85. 85.

    , , , & Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer 8, 129 (2008).

  86. 86.

    et al. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res. Treat. 96, 131–146 (2006).

  87. 87.

    et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 69, 565–572 (2009).

  88. 88.

    et al. High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients. Oncologist 17, 766–774 (2012).

  89. 89.

    et al. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Cancer Res. Treat. 134, 561–567 (2012).

  90. 90.

    et al. A gene expression signature of MEK pathway activation to predict survival in triple-negative breast cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), a1024 (2012).

  91. 91.

    et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov. 11, 873–886 (2012).

  92. 92.

    et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol. Cancer Ther. 11, 1143–1154 (2012).

  93. 93.

    et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin. Cancer Res. 15, 4649–4664 (2009).

  94. 94.

    et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 72, 3228–3237 (2012).

  95. 95.

    , , , & TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression. Oncol. Rep. 28, 567–575 (2012).

  96. 96.

    & Cancer epigenetics reaches mainstream oncology. Nat. Med. 17, 330–339 (2011).

  97. 97.

    , & Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol. Ther. 6, 64–69 (2007).

  98. 98.

    et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006).

  99. 99.

    et al. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res. 14, R79 (2012).

  100. 100.

    et al. Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Mol. Cancer Ther. 11, 973–983 (2012).

  101. 101.

    et al. Co-treatment with vorinostat synergistically enhances activity of Aurora kinase inhibitor against human breast cancer cells. Breast Cancer Res. Treat. 135, 433–444 (2012).

  102. 102.

    , , , & HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Lett. 307, 72–79 (2011).

  103. 103.

    et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 70, 3647–3656 (2010).

  104. 104.

    , & Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI) [abstract]. J. Clin. Oncol. 29 (Suppl. 27), a268 (2011).

  105. 105.

    et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012).

  106. 106.

    , & Timing is everything: order of administration of 5-aza 2' deoxycytidine, trichostatin A and tamoxifen changes estrogen receptor mRNA expression and cell sensitivity. Cancer Lett. 275, 178–184 (2009).

  107. 107.

    , & Targeting epigenetic readers in cancer. N. Engl. J. Med. 367, 647–657 (2012).

  108. 108.

    et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).

  109. 109.

    et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669–16674 (2011).

  110. 110.

    & Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin. Cancer Res. 16, 3526–3532 (2010).

  111. 111.

    et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 17, 461–469 (2011).

  112. 112.

    et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA 100, 8933–8938 (2003).

  113. 113.

    , , , & Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin. Cancer Res. 19, 610–619 (2013).

  114. 114.

    et al. Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell 20, 119–131 (2011).

  115. 115.

    , & Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat. Rev. Cancer 10, 825–841 (2010).

  116. 116.

    , & Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).

  117. 117.

    , , , & Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

  118. 118.

    et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555–567 (2007).

  119. 119.

    et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).

  120. 120.

    & Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 10, R25 (2008).

  121. 121.

    et al. Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics. J. Natl Cancer Inst. 102, 1637–1652 (2010).

  122. 122.

    et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).

  123. 123.

    et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).

  124. 124.

    et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009).

  125. 125.

    , & The response of CD24-/low/CD44+ breast cancer-initiating cells to radiation. J. Natl Cancer Inst. 98, 1777–1785 (2006).

  126. 126.

    et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).

  127. 127.

    et al. Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res. Treat. 128, 45–55 (2011).

  128. 128.

    & Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev. 3, 169–175 (2007).

  129. 129.

    , & Aberrant activation of notch signaling in human breast cancer. Cancer Res. 66, 1517–1525 (2006).

  130. 130.

    et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res. 68, 5226–5235 (2008).

  131. 131.

    et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br. J. Cancer 105, 796–806 (2011).

  132. 132.

    et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5, 168–177 (2009).

  133. 133.

    et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

  134. 134.

    , , , & Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res. 70, 5465–5474 (2010).

  135. 135.

    et al. Candidate genes in breast cancer revealed by microarray-based comparative genomic hybridization of archived tissue. Cancer Res. 65, 439–447 (2005).

  136. 136.

    , , & Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer. Oncol. Lett. 2, 995–1001 (2011).

  137. 137.

    et al. Hedgehog signaling is a novel therapeutic target in tamoxifen resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 72, 5048–5059 (2012).

  138. 138.

    , & The hedgehog pathway conditions the bone microenvironment for osteolytic metastasis of breast cancer. Int. J. Breast Cancer 2012, 298623 (2012).

  139. 139.

    , , , & Hedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolytic metastases. PLoS ONE 7, e34374 (2012).

  140. 140.

    , & Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clin. Cancer Res. 18, 2429–2435 (2012).

  141. 141.

    Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480 (2006).

  142. 142.

    et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl Acad. Sci. USA 100, 15853–15858 (2003).

  143. 143.

    et al. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 25, 1337–1342 (2004).

  144. 144.

    , , , & Expression of dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype. PLoS ONE 7, e37624 (2012).

  145. 145.

    & Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 1, 563–577 (2010).

  146. 146.

    et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

  147. 147.

    et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

  148. 148.

    et al. The Wnt inhibitor VS-507 reduces cancer stem cell (CSC) function in vitro and tumorigenicity in mice [abstract]. Cancer Res. 72 (Suppl. 1), LB-194 (2012).

  149. 149.

    et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149, 1284–1297 (2012).

  150. 150.

    & What signals operate in the mammary niche? Breast Dis. 29, 69–82 (2008).

  151. 151.

    et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

  152. 152.

    et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 71, 614–624 (2011).

  153. 153.

    , , , & Tumor-endothelial interaction links the CD44+/CD24 phenotype with poor prognosis in early-stage breast cancer. Neoplasia 11, 987–1002 (2009).

  154. 154.

    Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer. IUBMB Life 62, 268–276 (2010).

  155. 155.

    et al. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Cancer Res. 69, 466–474 (2009).

  156. 156.

    , & Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest. 121, 3804–3809 (2011).

  157. 157.

    et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 47, 570–584 (2012).

  158. 158.

    , , & Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

  159. 159.

    et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69, 1302–1313 (2009).

  160. 160.

    et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest. 120, 485–497 (2010).

  161. 161.

    et al. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res. Treat. 135, 737–747 (2012).

  162. 162.

    , , , & Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 11, R7 (2009).

  163. 163.

    et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 40, 650–655 (2008).

  164. 164.

    et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2, E7 (2004).

  165. 165.

    et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).

  166. 166.

    et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J. Pathol. 214, 357–367 (2008).

  167. 167.

    et al. Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells. Cancer Biol. Ther. 12, 924–938 (2011).

  168. 168.

    et al. The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through β1 integrin. Breast Cancer Res. Treat. 133, 459–471 (2012).

  169. 169.

    et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).

  170. 170.

    The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

  171. 171.

    et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

  172. 172.

    & Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).

  173. 173.

    et al. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer 8, 57 (2008).

  174. 174.

    et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8, 190–198 (2006).

  175. 175.

    et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

  176. 176.

    et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

  177. 177.

    et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

  178. 178.

    , & The rationale for targeting the LOX family in cancer. Nat. Rev. Cancer 12, 540–552 (2012).

  179. 179.

    et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

  180. 180.

    et al. LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 71, 1561–1572 (2011).

  181. 181.

    et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

  182. 182.

    et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

  183. 183.

    et al. Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO Mol. Med. 3, 528–544 (2011).

  184. 184.

    et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

  185. 185.

    Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).

  186. 186.

    & CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin. Cancer Res. 16, 2927–2931 (2010).

  187. 187.

    Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 13, 207 (2011).

  188. 188.

    et al. CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis. BMC Vet. Res. 8, 27 (2012).

  189. 189.

    et al. Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Res. 71, 603–613 (2011).

  190. 190.

    et al. The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast Cancer Res. Treat. 131, 837–848 (2012).

  191. 191.

    et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Res. 13, R47 (2011).

  192. 192.

    et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).

  193. 193.

    et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 72, 2768–2779 (2012).

  194. 194.

    et al. A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J. Surg. Res. 155, 231–236 (2009).

  195. 195.

    et al. Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone. Oncol. Rep. 21, 761–767 (2009).

  196. 196.

    et al. CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int. J. Cancer 129, 225–232 (2011).

  197. 197.

    et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).

  198. 198.

    & Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

  199. 199.

    & Integrin bi-directional signaling across the plasma membrane. J. Cell. Physiol. 228, 306–312 (2012).

  200. 200.

    , , & Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study. Diagn. Pathol. 7, 104 (2012).

  201. 201.

    et al. Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res. 8, R20 (2006).

  202. 202.

    , & Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways. Oncogene .

  203. 203.

    et al. Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model. J. Neurooncol. 110, 27–36 (2012).

  204. 204.

    et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489–502 (2006).

  205. 205.

    & Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).

  206. 206.

    et al. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97, 1573–1581 (2003).

  207. 207.

    , , , & BRCA1 tumours correlate with a HIF-1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression. Br. J. Cancer 101, 1168–1174 (2009).

  208. 208.

    et al. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res. Treat. 110, 465–475 (2008).

  209. 209.

    et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J. Mol. Med. 90, 803–815 (2012).

  210. 210.

    et al. The 2-nitroimidazole EF5 is a biomarker for oxidoreductases that activate the bioreductive prodrug CEN-209 under hypoxia. Clin. Cancer Res. 18, 1684–1695 (2012).

  211. 211.

    , , & Insight into the heterogeneity of breast cancer through next-generation sequencing. J. Clin. Invest. 121, 3810–3818 (2011).

  212. 212.

    et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).

  213. 213.

    et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

  214. 214.

    & Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov. 10, 351–364 (2011).

  215. 215.

    Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J. Clin. Oncol. 30, 898–901 (2012).

  216. 216.

    et al. A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), a508 (2012).

  217. 217.

    et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2012).

  218. 218.

    et al. SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2– metastatic breast cancer (MBC) [abstract]. J. Clin. Oncol. 30 (Suppl.), a510 (2012).

  219. 219.

    et al. A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors [abstract]. J. Clin. Oncol. 29 (Suppl.), a3028 (2011).

  220. 220.

    et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J. Clin. Oncol. 29, 4688–4695 (2011).

  221. 221.

    et al. A phase II study of foretinib in triple-negative, recurrent/metastatic breast cancer: NCIC CTG trial IND.197 (NCT01147484) [abstract]. J. Clin. Oncol. 30 (Suppl.) a1036 (2012).

  222. 222.

    et al. Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): results from a phase II randomized discontinuation trial (RDT) [abstract]. J. Clin. Oncol. 30 (Suppl.), a535 (2012).

  223. 223.

    et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin. Cancer Res. 14, 7138–7142 (2008).

  224. 224.

    et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br. J. Cancer 104, 1828–1835 (2011).

  225. 225.

    et al. Phase I trial of ixabepilone and vorinostat in metastatic breast cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), a1070 (2012).

  226. 226.

    et al. Phase II data for entinostat, a class 1 selective histone deacetylase inhibitor, in patients whose breast cancer is progressing on aromatase inhibitor therapy [abstract]. J. Clin. Oncol. 28 (Suppl. 15), a1052 (2010).

  227. 227.

    et al. Phase I study of panobinostat (LBH589) and letrozole in post-menopausal women with metastatic breast cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), e13501 (2012).

  228. 228.

    et al. A phase I study of panobinostat (LBH589) with capecitabine with or without lapatinib. J. Clin. Oncol. 28 (Suppl. 15), a1115 (2010).

  229. 229.

    et al. A phase 2 trial of dasatinib in patients with advanced HER2-positive and/or hormone receptor-positive breast cancer. Clin. Cancer Res. 17, 6897–6904 (2011).

  230. 230.

    et al. A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer. Ann. Oncol. 22, 2575–2581 (2011).

  231. 231.

    et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann. Oncol. 23, 610–617 (2012).

  232. 232.

    et al. Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin. Breast Cancer 11, 306–311 (2011).

  233. 233.

    et al. Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: preliminary phase II results [abstract]. J. Clin. Oncol. 30, a3010 (2012).

  234. 234.

    et al. Phase I study of abiraterone acetate (AA) in patients (pts) with estrogen receptor–(ER) or androgen receptor (AR)–positive advanced breast carcinoma resistant to standard endocrine therapies [abstract]. J. Clin. Oncol. 29 (Suppl.), a2525 (2011).

Download references

Acknowledgements

The authors thank Ahmad Awada for valuable scientific discussions before writing this manuscript.

Author information

Affiliations

  1. Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 121, 1000 Brussels, Belgium

    • Dimitrios Zardavas
    •  & Martine Piccart
  2.  Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

    • José Baselga

Authors

  1. Search for Dimitrios Zardavas in:

  2. Search for José Baselga in:

  3. Search for Martine Piccart in:

Contributions

All authors researched data for the article and made a substantial contribution to the discussion of the content. D. Zardavas wrote the article, and all authors edited the manuscript prior to submission.

Competing interests

J. Baselga acts as a consultant for AstraZeneca, Chugai, Genentech, Merck, Novartis, Roche. M. Piccart acts as a consultant for Amgen, Bayer, Roche-Genentech, PharmaMar and SanofiAventis. She receives honoraria from Amgen, Bayer, Novartis, Roche-Genentech, PharmaMar and SanofiAventis. D. Zardavas declares no competing interests.

Corresponding author

Correspondence to Martine Piccart.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrclinonc.2013.29

Further reading