• Contact Us
  • Indexing
  • Submit Manuscript
  • Open Access
  • Journals
  • Home
  • ISSN: 2373-9436
    J Cancer Biol Res 2(1): 1033.
    Submitted: 30 January 2014; Accepted: 03 March 2014; Published: 17 March 2014
    Special Issue entitled:
    Breast Cancer Therapeutics
    Short Communication
    Breast Cancer Agents: Treatment & Prevention
    Yong Zhao1*, Chengfeng Yang2, Sandra Z Haslam2 and Richard C Schwartz3
    1College of Chemistry & Pharmaceutical Sciences, Qingdao Agricultural University, China
    2Department of Physiology, Michigan State University, USA
    3Department of Microbiology and Molecular Genetics, Michigan State University, USA
    *Corresponding author: Yong Zhao, College of Chemistry & Pharmaceutical Sciences, Qingdao Agricultural University, China,
    The heterogeneous disease Breast Cancer (BC) is an ancient disease which was noted 3500 years ago by ancient Egyptians [1] .The heterogeneity, including intratumor heterogeneity and intertumor heterogeneity, is influenced by genetic and non-genetic factors. Furthermore, BC is the most common malignant tumor and the second leading cause of cancer death in women. Because BC is a heterogeneous disease, no single therapy is sufficient to treat all patients. In order to assess prognosis and determine the appropriate therapies for BC patients, many criteria like patient age, axillary lymph node status, tumor size, histological grade and lymphovascular invasion, hormone receptor status, and HER2 status have been used to categorize the disease. Based on recent molecular techniques, particularly gene expression profiling and immuno- histology, BC can be classified into four major types: estrogen and progesterone receptor positive luminal A and luminal B, HER2 and basal-like/triple negative BC [2]. If BC is diagnosed early, women have better prospects for survival. However, most women diagnosed with this disease will undergo systemic or local therapies to treat the disease. The therapies involve.
    Surgeons, radiation oncologists, medical oncologists and others working together to provide treatment. Surgery is the first line treatment. However, a variety of other medical therapies have also been used: radiotherapy, chemotherapy, hormonal therapy, bisphosphonate therapy and targeted biological therapy and others [3-12].
    Table 1 summarizes the agents which are approved by the USFDA to treat BC. There are four major common classes of agents for BC treatment: chemotherapy agents, hormonal therapy agents, bisphosphonate therapy agents, and targeted biological agents.
    Table 1 FDA approved agents for management of BC.



    Name of agents

    Mechanism of Action

    Chemotherapy Agents

    Alkylating Agents

    Cytoxan® / Cyclophosphamide Thiotepa

    Inserts an alkyl moiety into the DNA structure, which blocks cell division



    Adriamycin® / Doxorubicin

    Doxil® / Liposomal Doxorubicin Ellence® / Epirubicin

    Novantrone® / Mitoxantrone

    Disrupts duplex DNA structure, which blocks cell division


    Platinum Drugs

    Paraplatin® / Carboplatin

    Platinol® / Cisplatin

    DNA crosslinking that inhibits DNA repair mechanisms, leading to cell death



    Abraxane® / Paclitaxel Protein-bound

    Taxol® / Paclitaxel Taxotere® / Docetaxel

    Disrupts cellular microtubules to inhibit cell growth and stopcell division


    Vinca Agents

    Navelbine® / Vinorelbine

    Disrupts cellular

    microtubules to inhibit cell growth and stop cell division


    Other Chemotherapy Agents

    Adrucil® / Fluorouracil (5- FU)

    Camptosor® / Irinotecan Gemzar® / Gemcitabine




    Halaven® / Eribulin




    Ixempra® / Ixabepilone Methotrexate




    Temodar® / Temozolomide
















    Xeloda® / Capecitabine




    Evista® / Raloxifene

    Binds to estrogen receptors



    Fareston® / Toremifine

    to block estrogen activity



    Faslodex® / Fulvestrant

    and its associated growth-



    Nolvadex® / Tamoxifen

    promoting activities



    Arimidex / Anastrozole

    Inhibits aromatase to block



    Aromasin / Exemestane

    estrogen production



    Femara / Letrozole




    Lupron® / Leuprolide

    Reduces the ovarian



    Plenaxis® / Abarelix

    capacity to produce estrogen



    Suprefact® / Buserlin




    Zoladex® / Goserelin




    Megace® / Megestrol Acetate







    mone agents





    Actonel® / Risedronate

    Inhibits breast cancer bone

    ate Therapy


    Aredia® / Pamidronate




    Boniva® / Ibandronate




    Fosamex® /Alendronate




    Xgeva® /Denosumab




    Zometa® / Zoledronate




    Afinitor® / Everolimus

    Inhibits the mammalian




    enzyme target of rapamycin







    Avastin® / Bevacizumab

    Suppresses tumor growth by




    blocking angiogenesis to




    reduce the blood supply to






    Targeted Her2

    Herceptin® / Trastuzumab

    Monoclonal antibody; Inhibits cell division by




    blocking growth factors




    binding to Her2 receptor



    Kadcyla® / T-DM1 (Ado-

    A combination of Herceptin



    trastuzumab emtansine)

    and a chemotherapy drug




    (DM1) to inhibit cell growth



    Lapatinib® / Tykerb

    Blocks the HER2/neu

    Table 1 FDA approved agents for management of BC.

    (https://www.breastcancertrials.org/BCTIncludes/Resources/BreastCancerDrugs.html )
    Chemotherapy agents consist of systemic drug treatments intended to stop cancer cells dividing and growing [13-15]. There are 6 types of chemotherapeutic agents: alkylating agents, anthracyclines, platinum agents, taxanes, vinca agents, and other chemotherapeutic agents. Alkylating agents work by inserting an "alkyl group (CnH2n+1)" into the DNA structure to interfere with DNA replication and prevent cancer cells from dividing. The alkyl group is attached to the number 7 nitrogen atom of the purine ring of the guanine base of DNA. In general, cancer cells are proliferating faster with less active DNA error-correcting repair than healthy cells; therefore cancer cells are more sensitive to DNA damage. Anthracyclines, antibiotics derived from the bacterium Streptomyces peucetius var. caesius, attack cancer cells largely by disrupting DNA structure and preventing cell division. The anthracyclines are among the most effective anticancer agents ever developed and are effective against many types of cancer. However, they cause significant cardiotoxicity and neurotoxicity. Platinum agents, anti-cancer drugs that contain the metal platinum, cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks, or DNA protein crosslinks, all of which block DNA repair and/or DNA synthesis in cancer cells. These agents sometimes also included among alkylating agents because they have similar mechanisms as anti-cancer agents. Taxanes, mitotic inhibitors, act by interfering and disrupting the cellular microtubules. The microtubules play an important role in many cellular functions, including cell division. Taxanes are often used in combination with other chemotherapy agents. Vinca alkaloid agents, originally derived from the Periwinkle plant Catharanthus roseus, are a set of anti-mitotic and anti-microtubule agents. They are cell- cycle-specific cytotoxic drugs that inhibit the ability of cancer cells to divide by preventing the polymerization of tubulin into microtubules. There are also some chemicals agents that can be used to treat breast cancer, which do not belong to the aforementioned groups: Fluorouracil (5-FU), Irinotecan, Gemcitabine, Eribulin, Ixabepilone, Methotrexate, Temozolomide, Topotecan, Vincristine, Vinblastine, and Capecitabine. Collectively, all of these chemotherapeutic agents are often associated with unpleasant side effects because, in addition to cancer cells, they target all rapidly growing cells, including those in the gastrointestinal tract, bone marrow, testicles and ovaries [16,17].
    BC is a hormonally dependent disease in, at least, a proportion of patients [1,18]. Hormonal therapy agents, through manipulation of the endocrine system, inhibit production or activity of hormones (hormone antagonists), largely 17 β-estradiol, that promote tumor growth. These agents include anti-estrogen agents, aromatase inhibitors, ovarian suppression, and other Endocrine/Hormone agents. For patients with luminal A/B breast cancer, hormone-receptor positive (ER, PR-positive), hormone therapy with anti-estrogen agents (Raloxifene, Toremifine and Fulvestrant) and aromatase inhibitors (anastrozole, letrozole, exemestane) or ovarian suppression (in premenopausal patients) are the common strategies to treat this disease, often combined with other therapies [18].
    Bisphosphonate therapy agents, commonly used for osteoporosis, have been approved by FDA to treat Metastatic Breast Cancer (MBC) which has spread to the bones [19,20]. Bisphosphonate therapy agents may also be used in combinations with aromatase inhibitors for early stage breast cancer to lessen the adverse effect of aromatase inhibitors to weaken bone in some patients. This sub-class of agents includes risedronate, pamidronate, ibandronate, alendronate, denosumab and zoledronate.
    Targeted biological agents can selectively inhibit various mechanisms, include autocrine growth signals, continuous replicative potential, angiogenesis, and stromal invasion with the development of metastases. mTOR, angiogenesis and HER2 are among the targets for which these agents have been developed. HER2 positive breast cancer accounts for 20–25% of all breast cancer patients, and HER2 over expression deregulates activation of intracellular mitogenic signaling and leads to aggressive tumor behavior. The first drug to target HER2, Trastuzumab, is a recombinant humanized monoclonal antibody which binds to HER-2/neu protein to interfere with ligand binding and subsequent activation of the HER2 signaling pathway. Other FDA approved agents in this category include T-DM1, Tykerb and Pertuzuma, which work in different ways to block the HER2 pathway [21-23]. The vascular endothelial growth factor (VEGF) receptor family plays an essential role in angiogenesis that supports tumor growth. Therefore, targeting the VEGF pathway is another way to treat BC [24,25]. The FDA approved agent Bevacizumab is a monoclonal anti-body that can block angiogenesis in cancer. The mammalian target of rapamycin, mTOR, a human protein encoded by the MTOR gene, is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase protein family. The inhibitor everolimus interferes with cancer cell growth by blocking the mTOR pathway [26,27]. Resistance to anti-HER2 agents is a problem for targeted HER2 therapy. The resistance may be because of aberrant activation of signaling pathways downstream of the receptor, such as the presence of activating PI3K mutations or loss of function of the phosphatase PTEN or increase Rac1 activation. In our study we have found that inhibition of both Akt and Rac1 pathways resulted in a significantly more decrease of Trastuzumab resistance than inactivation of Rac1 or Akt alone [28]. Combination therapies are under investigation to overcome the resistance problem. In a recent Phase Ib study, paclitaxel, mTOR inhibitor everolimus and trastuzumab were combined together to treat the patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab [29].
    Basel like/Triple negative breast cancer, defined as tumors that are negative for Estrogen Receptor (ER), progesterone receptor (PR), and HER2, is a biologically aggressive disease with limited treatment options, in part due to the lack of these receptor targets. Chemotherapy is one treatment option [30].
    Chemoprevention has been defined by Sporn as "the use of pharmacologic or natural agents that inhibit the development of invasive breast cancer either by blocking the DNA damage that initiates carcinogenesis, or by arresting or reversing the progression of premalignant cells in which such damage has already occurred" [31]. Selective Estrogen Receptor Modulators (SERMs) and Aromatase Inhibitors (AIs) have been investigated as BC chemoprevention agents. While they are effective in prevention of endocrine responsive lesions, they have no effect in reducing the risk of estrogen receptor-negative BC. Tamoxifen and raloxifene are two effective agents used for the prevention of breast cancer in women at high risk for the development of the disease. Raloxifene has more side effects than tamoxifen. New agents are still under investigation for BC prevention [31-33].
    Even though progress has been made in BC diagnosis and treatment, BC is still a major health problem for women. The identification of new potential molecular targets and development of new agents to target these molecules in BC will have a significant impact on future BC therapy and provide a wealth of opportunities for chemoprevention also. There are many new targets currently being investigated, including the programmed death-1 (PD-1) pathway [34], protein phosphatase 2A(PP2A) [35], the BCL-2 pathway [36], cell cycle machinery [37], the quiescin sulfhydryl oxidase 1 (QSOX1) pathway [38], microRNA pathways [39] and some others [40-42].
    Also many novel delivery systems are currently being investigated: nano-particles, polymeric micelles, nano-micellar carriers, and others [43-45]. Even though the full mechanisms of action have not yet been elucidated, traditional Chinese herbal medicines have been used in disease prevention and treatment for centuries [46,47]. These agents may present alternative strategies to western cancer therapies. In addition, life styles decisions are likely also important factors for BC development, prevention and treatment. In a recent study in mice, we found that high fat diet initiated in puberty increases the breast cancer risk in adulthood [48].Other factors, including alcohol, tobacco, and cosmetics may also influence BC risk [47,49-52].
    The progress in breast cancer management requires multidisciplinary team efforts which involve basic researchers, radiologists, pathologists, surgeons, radiation oncologists, medical oncologists and psychologists. The development of rational, effective, and safe agents for prevention or treatment, involving targets in multiple regulatory pathways and with the ability to modify carcinogenesis in its early phases, will be desirable.
    1. Akram M, Siddiqui SA. Breast cancer management: past, present and evolving. Indian J Cancer. 2012; 49: 277-282.
    2. Schnitt SJ. Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol. 2010; 23 Suppl 2: S60-64.
    3. Keating P, Cambrosio A. 21st-century oncology: a tangled web. Lancet. 2013; 382: e45-46.
    4. Bilynskyj BT. The breast cancer treatment as a marker of progress in oncology. Exp Oncol. 2010; 32: 190-194.
    5. Huang M, Shen A, Ding J, Geng M. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol Sci. 2014; 35: 41-50.
    6. Chen TW, Bedard PL. Personalized medicine for metastatic breast cancer. Curr Opin Oncol. 2013; 25: 615-624.
    7. den Hollander P, Savage MI, Brown PH. Targeted Therapy for Breast Cancer Prevention. Front Oncol. 2013; 3: 250.
    8. Downs-Holmes C, Silverman P. Breast cancer: overview & updates. Nurse Pract. 2011; 36: 20-26.
    9. Chavez-MacGregor M, Gonzalez-Angulo AM. Breast cancer in 2012: New drugs, new knowledge, new targets. Nat Rev Clin Oncol. 2013; 10: 75-76.
    10. Engstrøm MJ, Opdahl S, Hagen AI, Romundstad PR, Akslen LA, Haugen OA, et al. Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients. Breast Cancer Res Treat. 2013; 140: 463-473.
    11. de Ruijter TC, Veeck J, de Hoon JP, van Engeland M, Tjan-Heijnen VC. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol. 2011; 137: 183-192.
    12. Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest. 2011; 121: 3797-3803.
    13. Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009; 32: 468-472.
    14. Blumenfeld Z. Chemotherapy and fertility. Best Pract Res Clin Obstet Gynaecol. 2012; 26: 379-390.
    15. Redden MH, Fuhrman GM. Neoadjuvant chemotherapy in the treatment of breast cancer. Surg Clin North Am. 2013; 93: 493-499.
    16. Munzone E, Curigliano G, Burstein HJ, Winer EP, Goldhirsch A. CMF revisited in the 21st century. Ann Oncol. 2012; 23: 305-311.
    17. O'Shaughnessy JA. Oral alkylating agents for breast cancer therapy. Drugs. 1999; 58 Suppl 3: 1-9.
    18. Abdulkareem IH, Zurmi IB. Review of hormonal treatment of breast cancer. Niger J Clin Pract. 2012; 15: 9-14.
    19. Gnant M. Anticancer activity of bisphosphonates in breast cancer. Anticancer Agents Med Chem. 2012; 12: 114-122.
    20. Liu Y, Zhao S, Chen W, Hu F, Zhu L, Zhang Q, et al. Bisphosphonate use and the risk of breast cancer: a meta-analysis of published literature. Clin Breast Cancer. 2012; 12: 276-281.
    21. Dent S, Oyan B, Honig A, Mano M, Howell S. HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials. Cancer Treat Rev. 2013; 39: 622-631.
    22. Boyraz B, Sendur MA, Aksoy S, Babacan T, Roach EC, Kizilarslanoglu MC, et al. Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Curr Med Res Opin. 2013; 29: 405-414.
    23. Vrbic S, Pejcic I, Filipovic S, Kocic B, Vrbic M. Current and future anti-HER2 therapy in breast cancer. J BUON. 2013; 18: 4-16.
    24. Kümler I, Nielsen DL. Trials of bevacizumab in breast cancer--a safety review. Expert Opin Drug Saf. 2012; 11 Suppl 1: S37-48.
    25. Wagner AD, Thomssen C, Haerting J, Unverzagt S. Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Database Syst Rev. 2012; 7: CD008941.
    26. Zagouri F, Sergentanis TN, Chrysikos D, Filipits M, Bartsch R. mTOR inhibitors in breast cancer: a systematic review. Gynecol Oncol. 2012; 127: 662-672.
    27. Barnett CM. Everolimus: targeted therapy on the horizon for the treatment of breast cancer. Pharmacotherapy. 2012; 32: 383-396.
    28. Zhao Y, Wang Z, Jiang Y, Yang C. Inactivation of Rac1 reduces Trastuzumab resistance in PTEN deficient and insulin-like growth factor I receptor overexpressing human breast cancer SKBR3 cells. Cancer Lett. 2011; 313: 54-63.
    29. Andre F, Campone M, O'Regan R, Manlius C, Massacesi C, Sahmoud T, et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol. 2010; 28: 5110-5115.
    30. Herold CI, Anders CK. New targets for triple-negative breast cancer. Oncology (Williston Park). 2013; 27: 846-854.
    31. Cazzaniga M, Bonanni B. Breast cancer chemoprevention: old and new approaches. J Biomed Biotechnol. 2012; 2012: 985620.
    32. Bozovic-Spasojevic I, Azambuja E, McCaskill-Stevens W, Dinh P, Cardoso F. Chemoprevention for breast cancer. Cancer Treat Rev. 2012; 38: 329-339.
    33. Files JA, Stan DL, Allen SV, Pruthi S. Chemoprevention of breast cancer. Womens Health (Lond Engl). 2012; 8: 635-646.
    34. McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013; 2: 662-673.
    35. Chen W, Wang Z, Jiang C, Ding Y. PP2A-Mediated Anticancer Therapy. Gastroenterol Res Pract. 2013; 2013: 675429.
    36. Oakes SR, Vaillant F, Lim E, Lee L, Breslin K, Feleppa F, et al. Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci U S A. 2012; 109: 2766-2771.
    37. Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D. Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother. 2014; 15: 407-420.
    38. Lake DF, F DO. The Emerging Role of QSOX1 in Cancer. Antioxid Redox Signal. 2013.
    39. Cho WC. Exploiting the therapeutic potential of microRNAs in human cancer. Expert Opin Ther Targets. 2012; 16: 345-350.
    40. Martin JL, de Silva HC, Lin MZ, Scott CD, Baxter RC. Inhibition of insulin-like growth factor binding protein-3 signaling through sphingosine kinase 1 sensitizes triple-negative breast cancer cells to EGF receptor blockade. Mol Cancer Ther. 2014; 13:316-328.
    41. Seoane S, Bermudez MA, Sendon-Lago J, Martinez-Ordoñez A, Abdul-Hadi S, Maestro M, et al. 26,26,26,27,27,27-Hexadeuterated-,25-Dihydroxyvitamin D3 (,25D-d6) As Adjuvant of Chemotherapy in Breast Cancer Cell Lines. Cancers (Basel). 2013; 6: 67-78.
    42. Karki R, Seagle BL, Nieves-Neira W, Shahabi S. Taxanes in combination with biologic agents for ovarian and breast cancers. Anticancer Drugs. 2014; 25: 536-554.
    43. Zhang X, Huang Y, Li S. Nanomicellar carriers for targeted delivery of anticancer agents. Ther Deliv. 2014; 5: 53-68.
    44. Rai M, Kon K, Ingle A, Duran N, Galdiero S, Galdiero M. Broad-spectrum bioactivities of silver nanoparticles: the emerging trends and future prospects. Appl Microbiol Biotechnol. 2014; 98: 1951-1961.
    45. Tan C, Wang Y, Fan W. Exploring polymeric micelles for improved delivery of anticancer agents: recent developments in preclinical studies. Pharmaceutics. 2013; 5: 201-219.
    46. You L, An R, Liang K, Wang X. Anti-breast cancer agents from Chinese herbal medicines. Mini Rev Med Chem. 2013; 13: 101-105.
    47. Santa-Maria CA, Stearns V. Statins and Breast Cancer: Future Directions in Chemoprevention. Curr Breast Cancer Rep. 2013; 5: 161-169.
    48. Zhao Y, Tan YS, Aupperlee MD, Langohr IM, Kirk EL, Troester MA, et al. Pubertal high fat diet: effects on mammary cancer development. Breast Cancer Res. 2013; 15: R100.
    49. Ellsworth RE, Valente AL, Shriver CD, Bittman B, Ellsworth DL. Impact of lifestyle factors on prognosis among breast cancer survivors in the USA. Expert Rev Pharmacoecon Outcomes Res. 2012; 12: 451-464.
    50. Alegre MM, Knowles MH, Robison RA, O'Neill KL. Mechanics behind breast cancer prevention - focus on obesity, exercise and dietary fat. Asian Pac J Cancer Prev. 2013; 14: 2207-2212.
    51. Magné N, Melis A, Chargari C, Castadot P, Guichard JB, Barani D, et al. Recommendations for a lifestyle which could prevent breast cancer and its relapse: physical activity and dietetic aspects. Crit Rev Oncol Hematol. 2011; 80: 450-459.
    52. Lambrechts S, Decloedt J, Neven P. Breast cancer prevention: lifestyle changes and chemoprevention. Acta Clin Belg. 2011; 66: 283-292.
    Cite this article: Zhao Y, Yang C, Haslam SZ, Schwartz RC (2014) Breast Cancer Agents: Treatment & Prevention. J Cancer Biol Res 2(1): 1033.
  • Current Issue Highlights
  • BRAT1 was originally identified as a BRCA1 interacting protein [1], however, subsequent studies showed that it also binds to ATM, DNA-PK, and SMC1,

    Mechanisms of detecting and repairing damaged DNA are conserved and controlled through the DNA damage response (DDR).

    JSciMed Central Peer-reviewed Open Access Journals
    About      |      Journals      |      Open Access      |      Special Issue Proposals      |      Guidelines      |      Submit Manuscript      |      Contacts
    Copyright © 2016 JSciMed Central All Rights Reserved
    Creative Commons Licence Open Access Publication by JSciMed Central is licensed under a Creative Commons Attribution 4.0 International License.
    Based on a work at https://jscimedcentral.com/. Permissions beyond the scope of this license may be available at https://creativecommons.org/.