Journal of Cancer Research and Treatment, 2015, Vol. 3, No.

2, 28-33
Available online at http://pubs.sciepub.com/jcrt/3/2/3
© Science and Education Publishing
DOI:10.12691/jcrt-3-2-3

Breast Cancer: Insights into Risk Factors, Pathogenesis,

Diagnosis and Management
Ahmed M. Kabel1,2,*, Fahad H. Baali1
1
Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
2
Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
*Corresponding author: drakabel@gmail.com
Received August 30, 2015; Revised September 11, 2015; Accepted September 13, 2015
Abstract Breast cancer is the most common invasive cancer in females worldwide. It usually presents with a
lump in the breast with or without other manifestations. Diagnosis of breast cancer depends on physical examination,
mammographic findings and biopsy results. Treatment of breast cancer depends on the stage of the disease. Lines of
treatment include mainly surgical removal of the tumor followed by radiotherapy or chemotherapy. Other lines
including immunotherapy, thermochemotherapy and alternative medicine may represent a hope for breast cancer
patients.
Keywords: breast, cancer, pathogenesis, diagnosis, management
Cite This Article: Ahmed M. Kabel, and Fahad H. Baali, “Breast Cancer: Insights into Risk Factors,
Pathogenesis, Diagnosis and Management.” Journal of Cancer Research and Treatment, vol. 3, no. 2 (2015): 28-
33. doi: 10.12691/jcrt-3-2-3.

Risk factors for breast cancer include female sex, older

age, genetics, lack of childbearing or lack of breastfeeding,
1. Introduction higher levels of estrogens, certain dietary patterns,
exposure to radiation, positive family history of breast
Breast cancer is cancer that develops from breast tissue. cancer and obesity. Tobacco smoking appears to increase
It is the most common invasive cancer in women [1]. the risk of breast cancer. In those who are long-term
Signs of breast cancer include a lump in the breast, a smokers, the risk is increased 35% to 50% [6,7,8]. Oral
change in breast shape, dimpling of the skin, nipple contraceptives might represent a predisposing factor for
discharge or a red scaly patch of skin [2]. Risk factors for the development of premenopausal breast cancer [9].
developing breast cancer include: female sex, obesity, lack There is a relationship between diet and breast cancer,
of physical exercise, drinkingalcohol, hormone replacement including an increased risk with a high fat diet, alcohol
therapy during menopause, ionizing radiation, early age at intake, obesity and high cholesterolintake [10,11]. Dietary
first menstruation and old age [3]. Breast cancer most iodine deficiency may also play a role [12].
commonly develops in cells lining the milk ducts and the Genetic susceptibility may play a significant role in the
lobules that supply the ducts with milk. There are more development of breast cancer by causing a hereditary
than 18 subtypes of breast cancer[4]. Diagnosis of breast breast–ovarian cancer syndrome. This includes those who
cancer is confirmed by taking a biopsy of the concerning carry the BRCA1 andBRCA2 gene mutation. Other
lump. Once the diagnosis is made, further tests are done to significant mutations include p53 (Li–Fraumeni syndrome),
determine if the cancer has spread beyond the breast and PTEN (Cowden syndrome), and STK11 (Peutz–Jeghers
which treatments it may respond to [2]. syndrome) [13]. Moreover, certain diseases of the breast
Medical treatment of breast cancer with antiestrogens such as atypical ductal hyperplasia and lobular carcinoma
such as tamoxifen or raloxifene may prevent breast cancer in situ, are correlated with an increased breast cancer risk.
in those who are at high risk of developing it [4]. Surgical Diabetes mellitus might also increase the risk of breast
removal of both breasts is another preventative measure in cancer [14].
some high risk women.In those who have been diagnosed Family history remains one of the most important risk
with cancer, various lines of treatment are used, including factors for the development of breast cancer [15]. Women
surgery, radiation therapy, chemotherapy, hormonal with a strong family history of breast cancer may inherit
therapy and targeted therapy. In those with distant some genetic mutations that modify the risk factors of the
metastasis, treatments are mostly aimed at improving disease and its clinicopathological features. The
quality of life and survival rate [5]. characteristics of familial breast cancer remain a
controversial issue as several studies have shown
inconsistent results [16]. Many studies have revealed that
2. Risk Factors for the Development of familial breast cancer has some specific clinical features
Breast Cancer compared to sporadic cases. It has been shown that
 Journal of Cancer Research and Treatment 29

women diagnosed with positive family history usually 5. Diagnosis of Breast Cancer
present an early age of onset, bilateral breast cancer,
advanced stage, lymph node involvement and negative Physical examination of the breasts by a healthcare
hormone receptors with a less favorable prognosis [17]. provider and mammography are considered as the primary
tools for diagnois of breast cancer [25]. Fine needle
aspiration and cytologycan also help to establish the
3. Pathophysiology of Breast Cancer diagnosis with a good degree of accuracy. Other types of
biopsy include core biopsy or an excisional biopsy, in
Breast cancer usually occurs due to an interaction which the entire lump is removed. Imaging techniques
between environmental and genetic factors. PI3K/AKT
such as ultrasound, computed tomography or magnetic
pathway and RAS/MEK/ERK pathway protect normal
resonance imaging are sufficient to give the physician
cells from cell suicide. When the genes encoding these
accurate diagnosis and staging of the disease [26].
protective pathways are mutated, the cells become
incapable of committing suicide when they are no longer
needed which then leads to cancer development. These 6. Classification of Breast Cancer
mutations were proven to be experimentally linked to
estrogen exposure [18]. It was suggested that Breast cancers are often classified by several systems
abnormalities in the growth factors signaling can facilitate which can affect the prognosis and the response to
malignant cell growth. Over expression of leptinin breast treatment. Description of a breast cancer optimally
adipose tissue leads to increased cell proliferation and includes all of these factors. They include histopathology,
cancer [19]. grade, stage, receptor status and DNA assays. Most breast
The familial tendency to develop breast cancers is cancers are derived from the epithelial lining of the ducts
called hereditary breast–ovarian cancer syndrome. Some or lobules, and these cancers are classified as ductal or
mutations associated with cancer, such as p53, BRCA1 lobular carcinoma. Carcinoma in situ is growth of
and BRCA2, occur in mechanisms to correct errors in precancerous cells within a particular part of the breast
DNA leading to uncontrolled division, lack of attachment, without invasion of the surrounding tissue. Invasive
and metastasis to distant organs. The inherited mutation in carcinoma, however, penetrates into the surrounding
BRCA1 or BRCA2 genes can interfere with repair of tissues and may be associated with distant metastasis [27].
DNA cross links and DNA double strand breaks [20]. Grading often compares the appearance of the breast
GATA-3 directly controls the expression of estrogen cancer cells to the appearance of normal breast tissue.
receptor (ER) and other genes associated with epithelial Cancerous cells are usually poorly differentiated or
differentiation. Loss of GATA-3 leads to inhibition of undifferented. Cell division becomes uncontrolled and cell
differentiation and poor prognosis due to increased cancer nuclei become less uniform. Pathologists describe cells as
cell invasion and distant metastasis [21]. well differentiated (low grade), moderately differentiated
(intermediate grade), and poorly differentiated (high grade)
as the cells progressively lose the features seen in normal
4. Clinical Presentation of Breast Cancer breast cells. Poorly differentiated cancers have the worst
prognosis [23].
The first presentation of breast cancer is typically a
Breast cancer staging using the TNM system is based
lump that is different from the rest of the breast tissue.
on the size of the tumor (T), whether or not the tumor has
Other presentations include thickening different from the
spread to the lymph nodes (N), and whether the tumor has
other breast tissue, one breast becoming larger or lower,
metastasis (M). Stage 0 is a pre-cancerous, either ductal
changein the position or shape of the nipples, skin carcinoma in situ or lobular carcinoma in situ. Stages 1–3
dimpling, nippledischarge, constant pain in part of the are within the breast or regional lymph nodes. Stage 4 is
breast or armpit or swelling beneath the armpit [22].
metastatic cancer that has the worst prognosis [25].
Inflammatory breast cancer is a particular type of breast
Breast cancer cells have receptors on their surface and
cancer that usually presents with itching, pain, swelling,
in their cytoplasm and nucleus. Chemical messengers such
nipple inversion, warmth and redness throughout the
as hormones bind to these receptors causing secondary
breast, as well as an orange-peel texture to the skin
changes in the cells These receptors include estrogen
referred to as peaud'orange. Paget's disease of the breast is
receptors (ER), progesterone receptors (PR) and HER2
another type of breast cancer that usually presents with
receptors. ER+ cancer cells depend on estrogen for their
redness, discoloration, or mild flaking of the nipple skin.
growth, so they can be treated with antiestrogens
Then, tingling, itching, increased sensitivity, burning pain
(e.g.tamoxifen). Untreated, HER2+ breast cancers are
and discharge from the nipple appear [23]. Phyllodes
generally more aggressive than HER2- breast cancers
tumors are hard, movable non-cancerous lumps formed [28].Cancers that do not have any of these three receptor
within the stroma of the breast and contain glandular as types are called triple-negative. They usually express
well as stromal tissue. They are classified on the basis of receptors for other hormones, such as androgens and
their appearance under the microscope as benign, prolactin [29].
borderline or malignant. Occasionally, breast cancer may
present as metastatic disease. Common sites of metastasis
include bone, liver, lung and brain. Symptoms depend on 7. Prevention of Breast Cancer
the site of metastasis and include unexplained weight loss,
fever, chills, bone pains, jaundice or neurological Proper control of body weight, drinking less alcohol,
symptoms [24]. physical exercises and breastfeeding are valuable
30 Journal of Cancer Research and Treatment

measures for reduction of the risk of breast cancer. Also, 8. Management of Breast Cancer
dietary consumption of omega-3 polyunsaturated fatty
acids and soya beans appears to reduce the risk [30]. The Management of breast cancer depends on many factors
selective estrogen receptor modulators (such as tamoxifen) including the stage of the cancer and the age of the patient.
reduce the risk of breast cancer but increase the risk of Breast cancer is usually treated with surgery, which may
thromboembolism and endometrial cancer. They are be followed by chemotherapy or radiation therapy, or both
recommended only for prevention of breast cancer in (Figure 1). Hormone receptor-positive cancers are often
women at high risk. The benefit of breast cancer reduction treated with hormone-blocking therapy over several years.
continues for at least five years after stopping these Monoclonal antibodies or other immunomodulators may
medications [31]. be given in advanced stages with distant metastasis [32].

Figure 1. Lines of treatment of breast cancer

treated. This darkening of the skin usually returns to

8.1. Surgery normal in one to two months after treatment. Other side
Depending on the stage and type of the tumor, just effects include muscle stiffness, mild swelling, breast
lumpectomy may be all that is necessary, or removal of tenderness and lymphedema. After surgery, radiation and
larger amounts of breast tissue may be necessary. Surgical other treatments have been completed, many patients
removal of the entire breast is called mastectomy [27]. notice the affected breast seems smaller. This is due to
Before lumpectomy, a needle-localization of the lesion removal of tissue during the lumpectomy operation [35].
with placement of a guidewire may be performed.
However, mastectomy may be the preferred treatment in 8.3. Systemic Therapy
multifocal cancer, breast previously treated with Systemic therapy uses medications to treat cancer cells
radiotherapy, large tumor relative to the size of the breast throughout the body. Systemic treatments include
and if the patient has any disease of the connective tissue chemotherapy, targeted therapy, immune therapy and
which may complicate radiotherapy. During the operation, hormonal therapy.
the lymph nodes in the axilla are also considered for
removal. If the removed tissue does not have clear 8.3.1. Chemotherapy
margins, further removal of a part of the pectoralis major Chemotherapy may be used before surgery, after
muscle may be needed [33]. surgery, or instead of surgery for inoperable cases. Patients
with estrogen receptor positive tumors will receive hormonal
8.2. Radiation Therapy therapy after chemotherapy is completed. Typical
Radiation therapy is an adjuvant treatment for most hormonal treatments include tamoxifen which is given to
women after lumpectomy or mastectomy. The purpose of premenopausal women to inhibit the estrogen receptors,
radiation is to reduce the chance of recurrence. Radiation aromatase inhibitors given to postmenopausal women to
therapy involves using high-energy X-rays or gamma rays lower the amount of estrogen in their systems and GnRH-
that target a tumor or tumor site. This radiation is very analogues for ovarian suppression in premenopausal
effective in killing cancer cells that may remain after women who are at high risk of recurrence [4].
surgery or recur where the tumor was removed [34].
Patients undergoing some weeks of radiation therapy 8.3.2. Targeted therapy
usually experience fatigue caused by the healthy tissue Breast cancer targeted therapy uses drugs that block the
repairing itself. Some breast cancer patients develop a growth of breast cancer cells in specific ways. For
suntan-like change in skin color in the exact area being example, in patients whose cancer overexpresses HER2
 Journal of Cancer Research and Treatment 31

protein, a monoclonal antibody known as trastuzumab is technique includes alternative to surgery, limiting hospital
used to block the activity of the HER2 protein in breast visits and reducing scarring [41]. Also, traditional herbal
cancer cells. In advanced cases, trastuzumab can be used medicine were used as adjunctive therapy for treatment of
in combination with chemotherapy to delay cancer growth breast cancer. They were proven, in combination with
and improve the patient's survival [36]. It was reported conventional therapy, to improve quality of life and
that the use of trastuzumab for up to one year delays the decrease the number of hot flashes per day [44]. Other
recurrence of breast cancer and improves survival [37]. lines of alternative therapy include group support therapy,
Other drugs used for targeted therapy include cognitive behavioral therapy, cognitive existential group
angiogenesis inhibitors (e.g. bevacizumab) that prevent therapy, a combination of muscle relaxation training and
the growth of new blood vessels leading to cutting off the guided imagery, thymus extract, transfer factor and
supply of oxygen and nutrients to cancer cells, signal melatonin. Encouraging but not fully convincing results
transduction inhibitors which block signals inside the were found for melatonin [45].
cancer cell that helps the cells to divide, stopping the
cancer from growing and antibodies for other
hormonereceptors such as androgen receptors and 9. Prognosis of Breast Cancer
prolactin receptors, which are present in a high proportion
of breast cancers [38]. Prognosis usually depends on many factors including
Flaxseed (The highest source of mammalian lignans) stage, grade, recurrence, age and health of the patient. The
was used in animal studies and led to reduction and stage of the breast cancer is the most important factor. The
regression of tumors. Intake of 25 grams of flaxseed daily higher the stage at diagnosis, the poorer the prognosis.
significantly reduced cell proliferation and increased The breast cancer grade is assessed by comparison of the
apoptosis in human breast cancer cells [39]. The breast cancer cells to normal breast cells. The closer to
preliminary research into flax seeds indicates that flax can normal the cancer cells are, the slower their growth and
significantly change breast cancer growth and metastasis, the better the prognosis. If cells are not well differentiated,
and enhance the inhibitory effect of tamoxifen on they will appear immature, will divide more rapidly, and
estrogen-dependent breast cancer [40]. will tend to spread [46].
The presence of estrogen and progesterone receptors in
8.3.3. Immunotherapy the cancer cell is important in guiding treatment. Those
The immune system can fightmany types of tumors who do not test positive for these receptors will not
including breast cancer.A new clinical trial is designed to respond to hormone therapy. Also, HER2 status affects
use oncofetal antigen (OFA) to recruit the patient's the prognosis of the disease. Patients whose cancer cells
ownimmune system to target and attack the cancer cells to are positive for HER2 have more aggressive disease and
improve patient survival and quality of life. Each patient may be treated with trastuzumab, a monoclonal antibody
will receive three monthly injections of the patient's own that affects this protein and improves the prognosis
dendritic cells that have been sensitized to OFA. It is [47,48].Younger women tend to have a poorer prognosis
anticipated that once the sensitized cells are injected back than post-menopausal women due to several factors.
into the patient, the patient's T-cells will locate the OFA Young women may be unaware of the changes that occur
found on the patient's cancer cells, thereby generating an in their breasts. So, they are usually at a more advanced
immune response with killing of the cancer cells and stage when diagnosed [49].
preventing further spread of the disease. Stimuvax is a
therapeutic cancer vaccine designed to induce an immune
response to cancer cells that express MUC1, a
10. Conclusion
glycoprotein antigen over-expressed on most cancers.
Breast cancer represents one of the most common
Stimuvax is thought to work by stimulating the body's
tumors in females worldwide. Its early diagnosis is the
immune system to identify and destroy cancer cells
first step for effective treatment. Treatment regimen
expressing MUC1 [41,42,43].
should consist of combination therapy to achieve high
8.3.4. Thermochemotherapy cure rate and decrease the risk of recurrence.
Medifocus heat treatment added to chemotherapy
increased the median tumor shrinkage in the References
thermochemotherapy arm to 88.4%, while for
chemotherapy alone the median tumor shrinkage was [1] Nelson, H.D., Smith, M.E., Griffin, J.C., Fu R., 2013. Use of
58.8%. For the thermo-chemotherapy treatment arm, medications to reduce risk for primary breast cancer: a systematic
almost 80% of breast tumors had a tumor volume review for the U.S. Preventive Services Task Force. Annals of
Internal Medicine 158: 604-14.
reduction of 80% or more, compared to only 20% for the [2] Brody JG, Rudel RA, Michels KB, Moysich KB, Bernstein L,
chemotherapy alone [41]. Attfield KR, et al., 2007. Environmental pollutants, diet, physical
activity, body size, and breast cancer: where do we stand in
8.3.5. Alternative and Adjunctive Treatments research to identify opportunities for prevention?. Cancer 109:
2627-34.
Recent studies have begun treating women suffering [3] Gøtzsche PC, Jørgensen KJ, 2013. Screening for breast cancer
from breast cancer with a procedure known as with mammography. The Cochrane database of systematic
cryoablation. The treatment freezes, than defrosts tumors reviews 6: CD001877.
using small needles so that only the harmful tissue is [4] Peng J, Sengupta S, Jordan VC, 2009. Potential of Selective
Estrogen Receptor Modulators as Treatments and Preventives of
damaged and ultimately dies.The advantage of this
32 Journal of Cancer Research and Treatment

Breast Cancer. Anti-Cancer Agents in Medicinal Chemistry 9: [27] Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB,
481-99. Edge SB, et al., 2009. Breast cancer: Clinical practice guidelines
[5] Reeder JG, Vogel VG, 2008. Breast cancer prevention. Cancer in oncology. JNCCN 7 (2): 122-192.
treatment and research 141: 149–64. [28] Sotiriou C, Pusztai L, 2009. Gene-expression signatures in breast
[6] Johnson KC, Miller AB, Collishaw NE, Palmer JR, Hammond SK, cancer. N Engl J Med 360 (8): 790-800.
Salmon AG, et al., 2011. Active smoking and secondhand smoke [29] Santana-Davila R, Perez EA, 2010. Treatment options for patients
increase breast cancer risk: the report of the Canadian Expert with triple-negative breast cancer. Journal of Hematology &
Panel on Tobacco Smoke and Breast Cancer Risk (2009).Tobacco Oncology 3: 42.
control 20 (1): e2. [30] Zheng JS, Hu XJ, Zhao YM, Yang J, Li D, 2013. Intake of fish
[7] Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, and marine n-3 polyunsaturated fatty acids and risk of breast
2012. Effect of physical inactivity on major non-communicable cancer: meta-analysis of data from 21 independent prospective
diseases worldwide: an analysis of burden of disease and life cohort studies. BMJ 346: f3706.
expectancy. The Lancet 380 (9838): 219-29. [31] Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S,
[8] Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell DeCensi A, et al., 2013. Selective oestrogen receptor modulators
MS, et al., 2015. Sedentary Time and Its Association With Risk in prevention of breast cancer: an updated meta-analysis of
for Disease Incidence, Mortality, and Hospitalization in Adults: A individual participant data. Lancet 381(9880): 1827-34.
Systematic Review and Meta-analysis. Annals of Internal [32] Saini KS, Taylor C, Ramirez AJ, Palmieri C, Gunnarsson U,
Medicine 162 (2): 123-32. Schmoll HJ, et al., 2011. Role of the multidisciplinary team in
[9] Gaffield ME, Culwell KR, Ravi A, 2009. Oral contraceptives and breast cancer management: results from a large international
family history of breast cancer. Contraception 80 (4): 372-80. survey involving 39 countries. Annals of Oncology 23 (4): 853-9.
[10] Blackburn GL, Wang KA, 2007. Dietary fat reduction and breast [33] Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW,
cancer outcome: results from the Women's Intervention Nutrition Blumencranz PW, et al., 2011. Axillary Dissection vs No Axillary
Study (WINS). The American journal of clinical nutrition 86 (3): Dissection in Women with Invasive Breast Cancer and Sentinel
s878-81. Node Metastasis: A Randomized Clinical Trial. JAMA 305 (6):
[11] Kaiser J, 2013. Cancer. Cholesterol forges link between obesity 569-575.
and breast cancer. Science 342 (6162): 1028. [34] Nelson JC, Beitsch PD, Vicini FA, Quiet CA, Garcia D, Snider
[12] Aceves C, Anguiano B, Delgado G, 2005. Is iodine a gatekeeper HC,et al., 2009. Four-year clinical update from the American
of the integrity of the mammary gland?. Journal of Mammary Society of Breast Surgeons MammoSite brachytherapy trial. The
Gland Biology and Neoplasia 10 (2): 189-96. American Journal of Surgery 198 (1): 83-91.
[13] Gage M, Wattendorf D, Henry LR, 2012. Translational advances [35] Yashar CM, Blair S, Wallace A, Scanderbeg D, 2009. Initial
regarding hereditary breast cancer syndromes. J surgoncol 105 (5): clinical experience with the Strut-Adjusted Volume Implant
444-51. brachytherapy applicator for accelerated partial breast irradiation.
[14] Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup Brachytherapy 8 (4): 367-72.
V,Wongwaisayawan S, Srinakarin J, et al., 2013. Risk factors of [36] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V.
breast cancer: a systematic review and meta-analysis. Asian Bajamonde A, et al., 2001. Use of Chemotherapy plus a
Pacific Journal of Public Health 25 (5): 368-87. Monoclonal Antibody against HER2 for Metastatic Breast Cancer
[15] Martin LJ, Melnichouk O, Guo H, Chiarelli AM, Hislop TG, That Overexpresses HER2. New England Journal of Medicine 344
Yaffe MJ, et al., 2010. Family history, mammographic density, (11): 783-792.
and risk of breast cancer. Cancer Epidemiol Biomarkers Prev; [37] Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja
19(2):456-63. V, Asola R, et al., 2006. Adjuvant Docetaxel or Vinorelbine with
[16] Tazzite A, Jouhadi H, Saiss K, Benider A, Nadifi S, 2013. or without Trastuzumab for Breast Cancer". New England Journal
Relationship Between Family History of Breast Cancer and of Medicine 354 (8): 809-820.
Clinicopathological Features in Moroccan Patients. Ethiopian [38] Hamid O,Sznol M,Pavlick AC,Kluger HM, Kim KB, Boasberg
Journal of Health Sciences; 23(2):150-157. PD,et al., 2010. Frequent dosing and GPNMB expression with
[17] Verkooijen HM, Chappuis PO, Rapiti E, et al., 2006. Impact of CDX-011 (CR011-vcMMAE), an antibody-drug conjugate (ADC),
familial risk factors on management and survival of early-onset in patients with advanced melanoma. Journal of Clinical Oncology
breast cancer: a population-based study. Br J Cancer; 94: 231–8. (Meeting Abstracts) 28(15_suppl): 8525.
[18] Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, [39] Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE, 2005.
Jankowiak R, et al., 2006. Catechol estrogen quinones as initiators Dietary Flaxseed Alters Tumor Biological Markers in
of breast and other human cancers: implications for biomarkers of Postmenopausal Breast Cancer.Clinical Cancer Research 11 (10):
susceptibility and cancer prevention. BiochimBiophysActa 1766 3828-3835.
(1): 63-78. [40] Wang L, Chen J, Thompson LU, 2005. The inhibitory effect of
[19] Jardé T, Perrier S, Vasson MP, Caldefie-Chézet F, 2011. flaxseed on the growth and metastasisof estrogen receptor
Molecular mechanisms of leptin and adiponectin in breast cancer. negative human breast cancer xenograftsis attributed to both its
Eur J Cancer 47 (1): 33-43. lignan and oil components. International Journal of Cancer 116 (5):
[20] Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas 793-798.
DC, et al., 2008. Variation of breast cancer risk among BRCA1/2 [41] Digianni LM, Garber JE, Winer EP, 2002. Complementary and
carriers. JAMA 299 (2): 194-201. alternative medicine use among women with breast cancer. J
[21] Kouros-Mehr H, Kim JW, Bechis SK, Werb Z, 2008. GATA-3 ClinOncol 20: 34S-38S.
and the regulation of the mammary luminal cell fate . Current [42] Hobohm U, 2009. Healing Heat: Harnessing Infection to Fight
opinion in cell biology 20 (2): 164-70. Cancer. American Scientist 97 (1): 34.
[22] Watson M, 2008. Assessment of suspected cancer. InnoAiT 1 (2): [43] Jaganti V, Das S, Sampath TS, 2011. A review on cancer vaccines.
94-107. International Journal of Pharma and Bio Sciences 2011; 2(3): 86-
[23] Zhang Y, Lv F, Yang Y, Qian X, Lang R, Fan Y, et al., 2015. 97.
Clinicopathological Features and Prognosis of Metaplastic Breast [44] Kim W, Lee WB, Lee JW, Min BI, Baek SK, Lee HS, et al., 2015.
Carcinoma: Experience of a Major Chinese Cancer Center. PLoS Traditional herbal medicine as adjunctive therapy for breast cancer:
One 10: e0131409. A systematic review. Complement Ther Med; 23(4):626-32.
[24] Lacroix M, 2006. Significance, detection and markers of [45] Ma C, Li LX, Zhang Y, Xiang C, Ma T, Ma ZQ, et al., 2015.
disseminated breast cancer cells. Endocrine-related Cancer Protective and sensitive effects of melatonin combined with
(Bioscientifica) 13 (4): 1033-67. adriamycin on ER+ (estrogen receptor)breast cancer. Eur J
[25] Saslow D, Hannan J, Osuch J, Alciati MH, Baines C, Barton M, et Gynaecol Oncol; 36(2):197-202.
al., 2004. Clinical breast examination: practical recommendations [46] Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F,
for optimizing performance and reporting. CA: a cancer journal Rakkhit R, Cardoso F, et al., 2009. High risk of recurrence for
for clinicians 54 (6): 327-344. patients with breast cancer who have human epidermal growth
[26] Yu YH, Liang C, Yuan XZ, 2010. Diagnostic value of vacuum- factor receptor 2-positive, node-negative tumors 1 cm or smaller. J
assisted breast biopsy for breast carcinoma: a meta-analysis and Clin Oncol 27 (34): 5700–6.
systematic review. Breast cancer research and treatment 120 (2): [47] Elston CW, Ellis IO, 1991. Pathological prognostic factors in
469-79. breast cancer. The value of histological grade in breast cancer:
 Journal of Cancer Research and Treatment 33

experience from a large study with long-term follow-up. [49] Azim HA, Santoro L, Russell-Edu W, Pentheroudakis G, Pavlidis
Histopathology 19 (5): 403-10. N, Peccatori FA, 2012. Prognosis of pregnancy-associated breast
[48] Robb C, Haley WE, Balducci L, Extermann M, Perkins EA, Small cancer: a meta-analysis of 30 studies. Cancer treatment reviews 38
BJ, et al., 2007. Impact of breast cancer survivorship on quality of (7): 834-42.
life in older women. Critical Reviews in Oncology/hematology 62
(1): 84-91.