Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx

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Letter to the Editor

Contents lists available at ScienceDirect

Journal of Reproductive Health and Medicine

jou r nal h o mep ag e: w ww .e lsev ier . co m / loc ate / j r hm

Can the risk of breast cancers be reduced in thisera of delayed first childbirths by treatment withhuman chorionic gonadotropin?

Breast cancers are the most common malignancies amongwomen worldwide.1 The incidence increases with age, but thedisease in older women is less aggressive than in younger women.1

It is estimated that there will be about 246,000 new cases and40,450 will die from the disease during 2016. However, deaths frombreast cancers are decreasing due to an early detection, discontin-uation of the use of only estrogen containing oral contraceptive pillsand estrogen replacement therapy for the control of menopausalsymptoms and choosing healthy life styles.1 Currently, there areabout 2.8 million breast cancer survivors in the U.S. alone.1

There are no broad-brush strokes to predict who might or mightnot develop breast cancer, because having risk factors does notnecessarily mean that the person will get the disease. Conversely,there is no guarantee that women will not develop the disease eventhough they do not seem to have any risk factors.1 The risk factorsfall into non-reproductive and reproductive categories.1 Non-reproductive risk factors are, age, individual’s and family history ofthe disease, radiation therapy of breast and chest, post-meno-pausal obesity and mutations in tumor suppressor genes such as,BRAC1, BRAC2 and others.1 About 5–10% of the breast cancer casesare due to heredity.1

The reproductive risk factors include, early menarche, latemenopause, never have given birth to a child (nulliparous) orgiving first childbirth at about 35 years of age or after, long-termuse of use of only estrogen containing oral contraceptive pills andestrogen replacement therapy.1 The common denominator amongthese risk factors is the length and cumulative exposure toendogenous or exogenous estrogens.

More and more young women across the world are waitinglonger than ever to have their first child.2,3 Cultural factors, socio-economic conditions and a level of education play an important rolein the decision making to postpone the first childbirth.3 The currentmean age of first time moms is 26 years in U.S., which is about a 5-year increase compared with 50 years ago.3 Moreover, the numberof first time moms who are older than 35 years is growing.3 Thesetrends are likely to continue and can be expected to influence thebreast cancer risk when women reach menopausal years.

Giving birth to a first child before 24 years age decreases thebreast cancer risk by about half, when women reach menopausalyears.4–7 Multi-parity, multiple pregnancies (twin or greater) andbreast-feeding can also decrease the risk.4–7 The pregnancybenefits are seen among women worldwide and they progressivelydecrease as the maternal age increases at the first childbirth.4–7

Thus, women who complete full term pregnancy at about 30 yearsof age will have the same risk as nulliparous women and those thatdelay until 35 years of age or older have an increased riskcompared with nulliparous women.4–7 The mechanisms behind

Please cite this article in press as: Rao CV. Can the risk of breast cancewith human chorionic gonadotropin?, J Reprod Health Med. (2016),

http://dx.doi.org/10.1016/j.jrhm.2016.08.001

2214-420X/� 2016 Elsevier, a division of Reed Elsevier India, Pvt. Ltd. All rights reserv

this age dependent progressive loss and reversal of pregnancybenefits are not known.

Russo and Russo et al. have provided an extensive evidence insupport of human chorionic gonadotropin (hCG) playing aprotective role against breast cancers.8 The work of others hasreaffirmed their findings. They include the presence of hCG/luteinizing hormone (LH) receptors in human breast cancer cellsand tissues and their activation resulting in an increase in celldifferentiation and apoptosis and a decrease in cell proliferation,invasion and survival.9–20 The hCG/LH receptors are required forthese hCG actions.15 Further support of these actions are thefindings that women with the receptor positive tumors tend tohave a longer metastasis free survival.21

Pregnancy and hCG treatment are equally effective in reducingthe breast cancer risk.8 Both of them induce permanent signaturegenomic imprinting and expression changes that are characterizedby low cell proliferation, increased cell differentiation which makethe cells resistant to carcinogenesis, increased efficiency of DNArepair mechanisms among others.22–27 These changes may explainhow decades after first pregnancy/hCG treatment can result in thereduced breast cancer risk during menopausal years.

These findings could provide clinical opportunities for hCG usein the risk reduction of breast cancers in this modern era ofincreasing number of women delaying their first child birth intotheir late 20 or 30 years of age. Since the delayed first childbirthincreases the breast cancer risk, these women would benefit fromsome kind of protection, so that they do not have to face theprospects of increased chances of developing the breast cancer,when they reach menopausal age. hCG could be useful in theprevention strategy. In order to develop the strategy, we mustanswer the following questions.

- What is the optimal hCG dose to use?- What is the minimal hCG treatment length to get the maximal

benefits?- What is the most effective mode of hCG delivery between

subcutaneous, intramuscular, intraperitoneal, intravenous orsublingual, as often used in hCG weight loss clinics?

- Whether nanoparticle delivery could make hCG therapy moreeffective?

We may be able obtain preliminary answers to these questionsin a rodent model. Once they are obtained, multinationalrandomized placebo controlled phase 1 clinical trials can beplanned by recruiting women volunteers of 24 years of age oryounger, who are planning to delay their first childbirth. Womenwho already have breast cancer or certain oncogene activatingmutations should be excluded from the trials, as there is evidencethat hCG could promote breast cancer growth.28

It is a daunting task to conduct phase 1 clinical trials and thenwait for several years to find out whether hCG treatment worked.

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Letter to the Editor / Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx2

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But there are no other choices to offer to young women, who havedecided to delay their first childbirth. Given the weight of theevidence, hCG administration may likely reduce the risk of breastcancers in this population. Other benefits to consider are the lowcost and minimal to no adverse side effects with hCG. Any minorinconveniences that women may have to face from the hCGadministration are a small price to pay for potential life time gain ofbenefits.

Finally, reducing the breast cancers risk by pharmacologicmimicking of pregnancy may not work for every woman, as nostrategy does. It is a lot of work, expense and time to conduct theseclinical trials. But we owe this to an increasing population of youngwomen in our societies, who are waiting longer than ever to havetheir first child.

References

1. American Cancer Society. Cancer Facts & Figures 2014. 2014. Atlanta, GA.2. Glick PC. Updating the life cycle of the family. J Marriage Fam. 1977;39:5–13.3. Average age of First-time Moms Climbing in the U.S. http://www.npr.org/

sections-shots/2016/01/14/462816458.4. MacMahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer risk. Bull

World Health Organ. 1970;43:209–221.5. Trapido EJ. Age at first birth, parity and breast cancer risk. Cancer. 1983;51:946–

948.6. Kalache A, Maguire A, Thompson SG. Age at last full-term pregnancy and risk of

breast cancer. Lancet. 1993;314:32–35.7. Rao CV. Does full term pregnancy at a young age protects women against breast

cancer through hCG? Obstet Gynecol. 2000;96:783–786.8. Russo J, Russo IH. Toward a physiological approach to breast cancer prevention.

Cancer Epidemiol Biomarkers Prev. 1994;3:353–364.9. Bernstein L, Hanisch R, Sullivan-Halley J, Ross RK. Treatment with human chorionic

gonadotropin and risk of breast cancer. Cancer Epidemiol Biomarkers Prev.1995;4:437–440.

10. Lei ZM, Rao Ch... Protective role of human chorionic gonadotropin and luteinizinghormone against breast cancer. In: Barnea ER, Jauniaux E, Schwarts PE, eds. In:Cancer & Pregnancy. Springer; 2001:209–215.

11. Jannssens JP, Russo J, Russo IH, et al. Human chorinic gonadotropin (hCG) andprevention of breast cancer. Mol Cell Endocrinol. 2007;269:93–98.

12. Toniolo P, Grankvist K, Wulff M, et al. Human chorionic gonadotropin in pregnancyand maternal risk of breast cancer. Cancer Res. 2010;70:6779–6786.

13. Liao X-H, Wang Y, Wang N, et al. Human chorionic gonadotropin decreases humanbreast cancer cell proliferation and promotes differentiation. IUBMB Life.2014;66:352–360.

14. Tao YX, Lei ZM, Rao CV. The presence of luteinizing hormone/human chorionicgonadotropin receptors in lactating rat mammary glands. Life Sci. 1997;60:1297–1303.

15. Lojun S, Bao S, Lei ZM, Rao CV. Presence of functional luteinizing hormone/chorionic gonadotropin (hCG) receptors in human breast cell lines: implicationssupporting the premise that hCG protects women against breast cancer. BiolReprod. 1997;57:1202–1210.

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16. Meduri G, Charnaux N, Loosfelt H, et al. Luteinizing hormone/human chorionicgonadotropin receptors in breast cancer. Cancer Res. 1997;57:857–864.

17. Hu YL, Lei ZM, Huang ZH, Rao CV. Determinants of transcription of the chorionicgonadotropin/luteinizing hormone receptor gene in human breast cells. Breast J.1999;5:186–193.

18. Jiang X, Russo IH, Russo J. Alternately spliced luteinizing hormone/human chori-onic gonadotropin receptor mRNA in human breast epithelial cells. Int J Oncol.2002;20:735–738.

19. Rao CV, Li X, Manna SK, Lei ZM, Aggarwal BB. Human chorionic gonadotropindecreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-B and AP-1 activation. J Biol Chem. 2004;279:25503–25510.

20. Lopez D, Sekharam M, Coppola D, Carter B. Purifies human chorionic gonadotropininduces apoptosis in breast cancer. Mol Cancer Ther. 2008;7:2837–2844.

21. Meduri G, Charnaux N, Spyratos F, Hacene K, Loosfelt H, Milgrom E. Luteinizinghormone receptor status and clinical pathologic, and prognostic features inpatients with breast carcinomas. Cancer. 2003;97:1810–1816.

22. Balogh GA, Heulings R, Mailo DA, et al. Genomic signature induced by pregnancy inthe human breast. Int J Oncol. 2006;28:399–410.

23. Belitskaya-Levy I, Zeleniuch-Jacquotte A, Russo J, et al. Characterization of agenomic signature of pregnancy identified in the breast. Cancer Prev Res.2011;4:1457–1464.

24. Russo J, Russo IH. Molecular basis of pregnancy-induced breast cancer prevention.Horm Mol Biol Clin Invest. 2012;9:3–10.

25. Santucci-Pereira J, George C, Armiss D, et al. Mimicking pregnancy as a strategy forbreast cancer prevention. Breast Cancer Manag. 2013;2:283–294.

26. Russo J, Santucci-Pereira J, Russo IH. The genomic signature of breast cancerprevention. Genes. 2014;5:65–83.

27. Barton M, Santucci-Pereira J, Russo J. Molecular pathways involved in pregnancy-induced prevention against breast cancer. Front Endocrinol. 2014;5:Article 213.

28. Iezzi M, Quaglino E, Cappello P, et al. hCG hastens both the development ofmammary carcinoma and the matastatization of hCG. LH and ERBB-2 receptor-positive cells in mice. Int J Immunopathol Pharmcol. 2011;24:621–630.

C.V. Raoa,b,*

aDepartment of Cellular Biology and Pharmacology, Herbert Wertheim

College of Medicine, Florida International University, Miami,

FL 33199, USAbDepartment of Molecular and Human Genetics and Obstetrics and

Gynecology, Reproduction and Development Program, Herbert

Wertheim College of Medicine, Florida International University,

Miami, FL 33199, USA

*Correspondence to: Department of Molecular and HumanGenetics and Obstetrics and Gynecology, Reproduction and

Development Program, Herbert Wertheim College of Medicine,Florida International University, Miami, FL 33199, USA

E-mail address: crao@fiu.edu (C.V. Rao).

Received 13 July 2016

rs be reduced in this era of delayed first childbirths by treatmenthttp://dx.doi.org/10.1016/j.jrhm.2016.08.001