“Current and Emerging Biomarker of Breast

Cancer”

National Institute of Food Science and TechnologyFaculty of Food, Nutrition and Home Sciences

University of Agriculture Faisalabad

RD-Fasiha Ahsan(Registered Dietitian)

1

Roadmap

2

Global and Pakistani scenario

Risk factors & diagnosis

Pathogenesis

Biomarkers: Established & Emerging

Influence of diet

Conclusion

References

Cancer: 2nd leading cause of death

~0.55 million women died in 2011 due to breast cancer

(WHO, 2013)

In US: estimated new cases of breast cancer were 0.23 million and deaths were 40,290

(ACA, 2016)

Mortality rate has increased from 12% in 1990 to 15% in 2013

(IHME, 2016)

3

Global Scenario

4

Pakistani Scenario

(WHO, 2014)

Pakistan's has highest rate of breast cancer amongst all Asian countries

Over 90,000 women suffer from breast cancer annually (Menhas and Umar, 2013)

1/9 women develop breast cancer at certain phase of their life

(SKMCH, 2015)

Incidence rate of breast cancer 2.5 times higher than neighboring countries

(Yasmeen and Zaheer, 2014)5

Pakistani Scenario

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Breast cancer: Risk Factors

(Abdulkareem, 2013)

Risk factors

Age,Gender

Overweight/ obese

Family history

Unhealthy diet

AlcoholTobacco

Night shift work

Lack of activity

7

Breast cancer: Diagnosis

(ACA, 2016)

Physical examination

Mammogram

Breast ultrasound

Nipple discharge

Biopsy Fine needle Surgical

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Breast cancer: PathogenesisParticipating factorsLack of activityObeseChemicals/ radiationsNight workAlcohol

Predisposing factorsGenderGenetic Early menarch

Response with carcinogens and damage DNA in breast cells

Prolonged injury cause mutation in p53gene

Loss of Apoptosis

Cancer promotion

In Breast Nipple invertOrange peelInflammationPain 

(Abdulkareem, 2013)

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Biomarker“A biomarker may be used to see how well the body

responds to a treatment for a disease or condition” (NCI, 2015)

Established biomarkers• p53 gene• HER2• BRCA1 & BRCA2

Emerging biomarkers• Ki-67• Cyclin D-1 (Sana and Malik, 2015)

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Cell cycle“Series of events taken place in cell leading to cell division, DNA duplication and formation of two daughter cells”

(Casimiro et al., 2013)

Cell cycle phasesG0 : Resting phaseG1 : Cell size increaseS : DNA replicateG2 : Cell growM : Division

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Established Biomarkers

Established Biomarkers : p53Important biomarker acts as: “tumor suppressor gene or guardian gene” Present on short arm of chromosome 17p

Act as transcriptional factor regulates cell cycle

If any stress on DNA then it will activate and initiate apoptosis

Mutation in p53 cause abnormal division of cells in breast (Lee et al., 2011)

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p53 process

DNA damage

p53 Activa-ted

p53 Activated

arrest cell cycle

initiate Apoptosis

eliminate damage cells

cell cycle restart

When p53 muted due to stress

Apoptosis can’t initiate

Uncontrolled division of damage cells in breast

Cancer occur

(Hosoda et al., 2014)

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Human Epidermal Growth Receptor 2 (HER2)

Important role in healthy breast formation

Glycoprotein present on long arm of chromosome 17q

Strong association between HER2 positive breast cancer and p53 mutations

Approximately, 71% of HER2 positive breast cancer patients contain mutated p53

(Misek and Kim, 2011)

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HER2 process

HER2 gene

When gene muted

More receptors start to form on breast

Receptors o

f

gene on

breast

Involve in cell division, growth and healthy breast formation

Breast cancer occur

Uncontrolled cell division

20,000 in normal cells

No=200,000

(Arteaga et al., 2014)

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BRCA1 & BRCA2 (BREAST CANCER SUSCEPTIBILTY GENE 1& 2) Present on chromosome 17q & 13q respectively

Involved in genome integrity and DNA repair

Hereditary breast cancer mostly due to the mutation in BRCA1 & BRCA2

Upto 30% breast cancer due to mutation in these genes

By the age of 70, 80% risk of cancer associated with BRCA1 and 50% with BRCA2 (Petrucelli et al., 2010)

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BRCA1 & BRCA2 process

BRCA1 & BRCA2Tumor suppressor genes

If only 1 muted genes inherited from parents

50% risk of breast cancer

Involve in DNA repair and integrity 

If these genes muted cancer occur

(Felix et al., 2014)

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Emerging Biomarkers

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Emerging Biomarker: Ki-67 Present on the long arm of chromosome 10q

Critical role in cell division and required for normal process of DNA

Basically a protein used as diagnostic tool

Use for quantification of proliferating cells

(Langosch et al., 2012)

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Ki-67 Expression varies in different phases of cell cycle Less in G1 and S phase (normal=6% ; cancer=10%) Rapidly increase in M phase (normal=10% ; cancer

20%) When it overexpressed cell divide more rapidly and if

untreated leading toward cancer

Ki-67 biomarker test is useful for early detection and treatment (Dowsett et al., 2011)

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Cyclin D1 Located on chromosome 11q Over-expressed and amplified in cancer When it amplifies cause changes in DNA of mammary

gland cells

CyclinD-1 gene amplify

Change in DNA of

mammary glands

Regulate downstream mechanism

Tumor-genesis

Abnormal cell

proliferationBreast

cancer

(Casimiro et al., 2013)

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Influence of diet on p53Vitamin C increase the p53 which increase apoptosis (Kim et al., 2012)

Selenium-containing protein SeMet can activate p53 in response to genetic damage & help in DNA repair

Tea, coffee and “smoky flavoring” could damage our DNA Contain chemicals: “pyrogallol and gallic acid” which

damage DNA and setting off p53 Pyrogallol is found in smoked foods as well as tea, cigarette

smoke and coffeeGallic acid is found in coffees and tea (Manna et al., 2009)

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Influence of diet on HER2Melatonin: found in almonds, cherries, tomatoes,

walnuts and oats induce apoptosis and reduce HER2 breast cancer

omega-3 and omega-6 polyunsaturated fatty acid ratio in the diet reduced risk of cancer

The combination of DHA & curcumin more effective in increasing apoptosis

Red meat consumption reduce circulating melatonin

(Ledesma, 2015)

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Influence of diet on BRCA1 & BRCA 2Many foods reduced risk of breast cancer in BRCA1 &

BRCA2 carriers include:Cabbage, cauliflower, broccoli, kale, soybeans, tomatoes, walnuts etc.

Meat consumption preferentially increased breast cancer risk in BRCA2 carriers

Breast cancer risk increased in heavy coffee drinkers who were BRCA1 carriers

(Ledesma, 2015)

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Influence of diet on Ki-67 & Cyclin D-1Ki-67

Many foods contain compounds which reduce gene expression by promoting apoptosis

Important are: onions, garlic, cruciferous vegetables, fish etc.

(Ledesma, 2015)

Cyclin D-1 Dietary fat increase its expression Reduce fat and use low SFAs will reduce cancer risk (Kim et al., 2011)

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Conclusion

Screening: Breast self-examination (BSE) p53 is most important among established biomarkers Ki-67 important in emerging biomarkers Increase intake of fruits, vegetables, whole grains and

nuts Decrease intake of fat and smoked foods Maintain healthy weight through balance dietPerson who eat balance diet and avoid sedentary lifestyle

not only prevent cancer but also other chronic diseases

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References ACA (American Cancer Society). 2016. Cancer Facts and Figures. American

Cancer Society Inc. Atlanta, GA, USA.ACA (American Cancer Society). 2016. Breast Cancer Diagnosis. American

Cancer Society Inc. Atlanta, GA, USA. Abdulkareem, I.H. 2013. A review on pathogenesis of breast cancer. J. Genet.

Syndr. Genet. Ther. 4:1-4. Arnold, A. and A. Papanikolaou. 2010. Cyclin D1 in breast cancer pathogenesis.

J. Clin. Oncol. 23:4215‑4224.Arteaga, C.L., M.X. Sliwkowski, C.K. Osborne, E.A. Perez, F. Puglisi and L.

Gianni. 2012. Treatment of HER2‑positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9:16‑32.

Casimiro, M.C., M. Crosariol, E. Loro, Z. Li and R.G. Pestell. 2013. Cyclins and cell cycle control in cancer and disease. Genes Cancer. 3:649-657.

Dowsett, M., T.O. Nielsen, J. Bartlett, R. C. Coombes, J. Cuzick, M. Ellis, J.C. Hugh and D.F. Hayes. 2011. Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group. J Natl. Cancer Inst. 103:1-9.

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References Felix, G.E.S., C.A. Sandes, R.S.C. Guindalini, R. Meyer, M. Romeo, L.

Nascimento and K.A. Sandes. 2014. Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population. Human Genome Variation. 1:14012. doi:10.1038/hgv.2014.12

Hosoda, M., M. Yamamoto, K. Nakano, K.C. Hatanaka, E. Takakuwa and Y. Hatanaka. 2014. Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre‑ and postmenopausal women with estrogen receptor‑positive breast cancer. Breast Cancer Res. Treat. 144:249‑261.

IHME (Institute for Health Metrics and Evaluation). 2016. New cancer cases rise globally, but death rates are declining in many countries. Institute for Health Metrics and Evaluation, Seattle, WA, USA.

Kim, J., S.D. Lee, B. Chang, D.H. Jin, S. Jung, M.Y. Park, Y. Han and M.S. Lee. 2012. Enhanced antitumor activity of vitamin C via p53 in cancer cells. Free Radic. Biol. Med. 53:1607-1615.

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References Kim, E.J., M.R. Choi, H. Park, M. Kim, J.E. Hong, K.W. Lee and J.H.Y. Park.

2011. Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice. Breast Cancer Res. Treat. 13:R78.

Langosch, K., T. Karn, V. Muller, I. Witzel, A. Rody, M. Schmidt and R.M. Wirtz. 2012. Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. Breast Can. Res Treat. 137:57-67. 

Lee, D.S., S.H. Kim, Y.J. Suh, S. Kim, H.K. Kim and B.Y. Shim. 2011. Clinical implication of p53 overexpression in breast cancer patients younger than 50 years with a triple‑negative subtype who undergo a modified radical mastectomy. Jap. J. Clin. Oncol. 41:854‑66.

Ledesma, N. 2015. Nutrition and Breast Cancer. University of California, San Francisco, CA, USA.

Manna, S., S. Mukherjee, A. Roy, S. Das and C.K. Panda. 2009. Tea polyphenols can restrict carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1. J. Nutr. Bio. 20:337-349.

Menhas, R. and S. Umer. 2013. Breast Cancer among Pakistani Women. Iran J. Public Health. 44:586-587.

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References Misek, D.E. and E.H. Kim. 2011. Protein biomarkers for the early detection of

breast cancer. Int. J. Proteomics. doi:10.1155/2011/343582. NCI (National Cancer Institute). 2015. NCI dictionary of cancer terms.

National Cancer Institute, Rockville, Maryland, USA. Petrucelli, N., M.B. Daly and G.L. Feldman. 2010. Hereditary breast and

ovarian cancer due to mutations in BRCA1 and BRCA2. Genet. Med. 12:245-259.

SKMCH (Shaukat Khanum Memorial Cancer Hospital). 2015. Breast cancer. Available from: https://www.shaukatkhanum.org.pk/news-a-events/events/228.html. Accessed on: February 18, 2016.

Sana, M. and H.J. Malik. 2015. Current and emerging breast cancer biomarkers. J. Can. Res. Ther.11:508-513.

WHO (World Health Organization). 2013. Breast Cancer Burden. World Health Organization. Geneva, Switzerland.

WHO (World Health Organization). 2014. World Health Rankings: Breast Cancer. World Health Organization. Geneva, Switzerland.

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References Yasmeen, F. and S. Zaheer. 2014. Functional time series models to estimate

future age‑specific breast cancer incidence rates for women in Karachi, Pakistan. J. Health Sci. 2:213‑221.

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