Understanding Breast Cancer

Compiled by John G. Connor, M.Ac., L.Ac. Edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
Introduction

Research on Natural Compounds that May be Beneficial in Breast Cancer
Examples of Chemotherapeutic Agents Used in Breast Cancer
Breast Cancer and Bone Metastasis
Research on Natural Compounds that May be Beneficial in Bone Cancer
References

Introduction
Breast cancer is the most common type of malignancy diagnosed in women with more than 180,000 estimated new cases in USA in 2008. Almost one third (32%) of all cancers diagnosed in women are breast cancer. (Miele et al 2009)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Research on Natural Compounds that May beBeneficial in Breast Cancer
1.    Andrographolide – posseses potent anti-tumor actions against breast cancer. (Zhi 2007) (Zhen 2007)
2.    Black cohosh – A population-based case control study involving 949 breast cancer cases found that use of black cohosh had a significant breast cancer protective effect. (Rebbeck et al 2007)
3.    Carotenoids – A nested case-control study of 295 cases found that carotenoids may protect against the development of breast cancer. (Sato et al 2002)
4.   Coenzyme Q(10), Riboflavin and Niacin (CoRN) – Tamoxifen on coadministration with CoRN has a favorable impact on various blood chemistry profiles. However, large scale randomized studies over a longer time span are required to ascertain the safety and efficacy of co-administrating antioxidants with conventional chemotherapy. (Yuvaraj et al 2008)
5.    Curcumin – In addition, curcumin exerts strong anti-invasive effects in vitro that are not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells.  These anti-invasive effects appear to be mediated through the downregulation of MMP-2 (matrix metalloproteinase) and the upregulation of TIMP-1 (tissue inhibitor of metalloproteinase), 2 common effector molecules that have been implicated in regulating tumor cell invasion. This study also demonstrates that curcumin inhibits the transcript levels of 2 major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) mainly in ER-negative MDA-MB-231. (Shao et al 2002)
6.    Curcumin – The inhibition of cell growth and induction of apoptosis by curcumin in MCF-7 breast cancer cells might be mediated, at least partially, by its ability to down-regulate the insulin-like growth factor-1 (IGF-1) axis. (Yangqui et al 2007) 7.    Curcumin inhibits cell proliferation of MDMA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFκB, cyclin D and MMP-1 transcription.  (Liu et al 2009)
8.    DIM synergizes with chemotherapeutic agents by inhibiting multi-drug resistance through downregulation of P-glycoprotein (P-gp), and is a potent chemopreventive agent for hormonal-dependent cancers such as breast, prostate and cervical cancer. (Aggarwal and Ichikawa, 2005)
9.    Fish oil – In a study involving 980 cases of incident invasive breast cancers it was found that current use of fish oil was associated with reduced risk of breast cancer. Ten-year average use was suggestive of reduced risk. These results held for ductal but not lobular cancers. (Brasky et al 2010)
10.   Ginseng – In a study involving 1,455 breast cancer patients it was found that ginseng use after cancer diagnosis, particularly current use, was positively associated with QOL (Quality of Life) scores, with the strongest effect in the psychological and social well-being domains. Additionally, QOL improved as cumulative ginseng use increased. (Cui et al 2006)
11.   Honokiol – Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. (Crane et al 2009)
12.   Honokiol inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest.  (Wolf et al, 2007)
13.   I-3-C (indole-3-carbinol) – which converts into DIM, induced marked reduction of EGFR in human breast cancer cell lines prior to cell death. (Moiseeva, Heukers & Manson 2006)
14.   Mistletoe – 3 controlled human studies using viscum album (mistletoe) extracts reported statistically significant benefit in women with breast of gynecological cancer. (Kienle et al 2009)
15.   Omega-3 fatty acids – Diets high in omega3 fatty acids exert suppressive effects on cancer growth and are associated with impaired angiogenesis.  Both EPA and DHA have shown to inhibit metastasis of several cancer cell lines including breast, prostate and colon cancer.  For example, one study found that total n-6 poly-unsaturated fatty acids may be contributing to the high risk of breast cancer in the United States and that specific long chain n-3 poly-unsaturated fatty acids derived from fish oils may have a protective effect. (Bagga et al 2002)
16.   Resveratrol – IGF-II is a potent mitogen and inhibitor of apoptosis in breast cancer. Resveratrol regulates insulin-like growth factor-II (IGF-II) in breast cancer cells.  (Vyas, Asmerom and DeLeon, 2005)

· Abraxane – Breast Cancer: the relative efficacy of Abraxane was significantly higher compared with taxol in HER2-negative tumors (three of three) and in HER2-positive tumors with high levels of SPARC*. (Anticancer Drugs. 2008 Oct;19(9):899-909)
o SPARC (Secreted Protein Acidic Rich in Cysteine) is an extracellular matrix protein found in the tumor cell surface and which is rapidly internalized into the tumor cell.
o Patients with SPARC-positive tumors, that is, those with the worst prognosis, will respond favorably to Abraxane therapy, whereas other taxanes will not. (Transl Oncol. 2009 May;2(2):59-64)

· Aromasin – an aromatase inhibitor.
o Loss of E-cadherin expression is associated with better response to aromatase inhibitors versus tamoxifen. (Borley et al 2008)

· Herceptin – is a monoclonal antibody.o PTEN is essential to long-term success with Herceptin, i.e., inactivation of PTEN causes resistance to Herceptin. 
o Single nucleotide polymorphisms associated with herceptin include:  P95HER2, EGF, IGFIR & PI3-K.
o Used for metastatic HER2 positive breast cancer. 

· Tamoxifen – an anti-extrogen/SERM.
o Single nucleotide polymorphisms associated with tamoxifen include: CYP2D6, BRCA1, Pak1, A1B1 & HER-2, CK-19, AP-1, CYP17.
o Upregulation of Met expression in breast cancer cells promotes resistance to the Erb B2-targeted TAM antibody (Shattuck 2008). 
o Combined HerII & ER expression predicts TAM resistance.
o Loss of E-cadherin expression is associated with better response to aromatase inhibitors vs. TAM. (Borley 2008)
o Tamoxifen use is associated with increased risk of venous thrombo-embolism, pulmonary embolism and stroke, endometrial cancer and uterine sarcoma.

· Tykerb (Lapatinib) -. Is a small tyrosine kinase inhibitor.
o Tykerb crosses the blood brain barrier. It is used with herceptin & Xeloda.
o It targets Her2 & Her1.

· Xeloda – is a nucleic acid blocker, an anti metabolite.
o Lower levels of MTHFR correspond to less toxicity of Xeloda at standard dosing. (Etienne-Grimaldi 2007).
o MTHFR, thymidylatesynthase (TS), and dihydropyrimidinedehydrogenase (DPD), relate to resistance and increased toxicity of 5FU and Xeloda. Clin Cancer Res 2006;12 (18 ) September15, 2006 DPD (Dihydropyrimidine dehydrogenase) is the 1st and rate-limiting enzyme in the pathway involved in the degradation of pyrimidine bases uracil and thymine. DPD is responsible for catabolism of 5-fluorouracilo MTHFR C677T and A1298C mutations are associated with increased toxicity and side effects of methotrexate 5-FU/ Xeloda, as well as Almita. Ann Rheum Dis. 2004;63(10): 1227-31. Br J Cancer. 2004;90(2):526-34o If thymidylate synthase is low it shows us that Xeloda is useful.
o Xeloda use is associated with ischemia, pericarditis and CHF.  

Breast Cancer and Bone Metastasis
   
In spite of advances in treatment strategies, about 25%-40% of patients with breast cancer still eventually develop metastatic disease. The choice of the optimal therapeutic strategy for patients with metastatic disease is largely influenced by prior exposure to adjuvant therapies. (Guarneri and Conte, 2009)

Ki-67 – The Ki-67 monoclonal antibody is used to determine the proliferation state of breast cancer, bone cancer, brain tumors, cervical cancer, colorectal cancer, endometrial cancer, liver tumors, lymphomas.  Laboratory Tests and Diagnostic Procedures, pp.689-690  (2008)

· Matrix metalloproteinase MMP-7, in human breast-to-bone metastases. We proposethat the solubilization of RANKL by MMP-7 is a potential mechanismthrough which MMP-7 mediates mammary tumor–induced osteolysis.Our studies indicate that the selective inhibition of MMP-7in the tumor-bone microenvironment may be of benefit for thetreatment of lytic breast-to-bone metastases. (Thiolloy et al, 2009)

· It was found that transforming growth factor beta receptor 1 (TGF-βR1) is a commonly upregulated gene at the tumor bone interface.  These studies demonstrate that inhibition of TGF-βR1 signaling at the tumor bone interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis.  (Futakuchi, et al, 2009)
 
Research on Natural Compounds that May be Beneficial in Bone Cancer
1.    I-3-C demonstrated an ability to inhibit breast cancer bone metastasis by down-regulating MMP-9 & NF-κB. (Mol Cancer Ther 2006)

2.    Resveratrol – In one study it was shown that resveratrol’s antiproliferative effects on osteosarcoma cells are mediated by the activation of the ERKs/p53 signaling pathway and therefore identifies new targets for strategies to treat and/or prevent osteosarcoma.  (Alkhalaf and Jaffal, 2006)

References

1.    Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005
2.    Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010
3.    Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001
4.    Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996
5.    Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008
6.    Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257
7.    Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281
8.    Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006
9.    McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002
10.   Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009
11.   Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008
12.   Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000
13.   Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010
14.   Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-309-7753.

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