RESEARCH SYNTHESIS Induced Abortion and Breast Cancer Angela Lanfranchi, M.D., and Patrick Fagan, Ph.D. February 2014 I. Introduction: Induced abortion increases breast cancer risk In the past 30 years, landmark advances in developmental and molecular breast biology coupled with multiple epidemiologic studies from around the world have shown induced abortion to be an independent risk factor for breast cancer. Induced abortion before 32 weeks’ gestation will impede the natural maturation process in the breast such that there is a significantly greater probability that breast cancer will develop later. Those most at risk of developing breast cancer after an abortion include teenagers (almost half of all first induced abortions between 2006 and 2010 were reportedly to teenagers1) and women over 30, especially if they have a family history of breast cancer.2 A 2013 study published in the Journal of the American Medical Association3 found an alarming increase in “distant” breast cancer among women aged 25 to 39. “Distant” breast cancer is breast cancer that has metastasized “remote[ly]… ([to the] bone, brain, lung, etc).”4 This rise in breast cancer incidence amounted to an increase of 2 percent 1Marriage and Religion Research Institute, Demographics of Women Who Have Had an Abortion: from the National Survey of Family Growth 2006-2010, by Patrick Fagan and Scott Talkington (2013): 8. www.marri.us/abortion- demographics (accessed August 7, 2013). Note that teenagers procured about 18 percent of all induced abortions in 2008. Guttmacher Institute, Characteristics of U.S. Abortion Patients, 2008, by Rachel K. Jones, Lawrence B. Finer, and Susheela Singh, 2010. 2Janet R. Daling, Kathleen E. Malone, Lynda F. Voigt, Emily White, and Noel S. Weiss, “Risk of Breast Cancer among Young Women: Relationship to Induced Abortions,” Journal of the National Cancer Institute86 (1994): 1584- 1592. 3Rebecca H. Johnson, Franklin L. Chien, and Archie Bleyer, “Incidence of Breast Cancer With Distant Involvement among Women in the United States, 1976 to 2009,” Journal of the American Medical Association309, no. 8 (2013): 800-805. 4Rebecca H. Johnson, Franklin L. Chien, and Archie Bleyer, “Incidence of Breast Cancer With Distant Involvement among Women in the United States, 1976 to 2009,” Journal of the American Medical Association309, no. 8 (2013): 800. MARRI 801 G St. NW Washington, DC 20001 202.393.2100 marri.us/abortion-breast-cancer per year from 1976 to 2009,5 and it persisted across three different sets of National Cancer Institute data.6 A review of National Cancer Institute cancer data7 shows invasive breast cancer incidence was 24 percent higher in 2007 than in 1976. At its peak over that period, in 1999, invasive breast cancer incidence was almost 40 percent higher than in 1976. These data show an increase of over 400 percent in in situ breast cancer incidence among women under age 50 between 1976 and 2007. An approximately 560 percent increase in in situ breast cancer incidence occurred among women of all ages over the same period. The study published in the Journal of the American Medical Association makes little attempt to empirically determine the source of this increase in breast cancer incidence among younger women. However, that the increase is occurring is reason enough to study more carefully the increased vulnerability to breast cancer that we think induced abortion confers on women. Given what is known of breast physiology and the reproductive risks described in standard medical texts,8 it is most natural that induced abortions would cause an increase in the risk of breast cancer. It has been known for centuries that remaining childless increases a woman’s risk for breast cancer; conversely, it has also been known that pregnancy is protective. In 1743, Ramazzini of Padua observed that there was a higher incidence of breast cancer among nuns.9 Nuns were largely childless, whereas the rest of the population had pregnancies early in their reproductive lives. No matter the length of her pregnancy (save those that end in first-trimester spontaneous abortions10), until 32 weeks’ gestation, a woman will experience changes in her breast tissue that will increase her risk of breast cancer. However, the epigenetic changes that occur in the breast lobules during a pregnancy lasting more than 32 weeks                                                              5 When broken down, women aged 25 to 34 were found to have a slightly larger annual percent increase in risk than women aged 35 to 39. Among women aged 25 to 39, the increased risk was significant and pronounced among black women, as well as among non-Hispanic white women and women residing in metropolitan areas, though fewer years of data were available for this analysis. 6 SEER (the program that collected the referenced data), or the Surveillance, Epidemiology, and End Results Program, is a program of the National Cancer Institute. 7 National Cancer Institute, SEER Cancer Statistics Review, 1975-2007, by S.F. Altekruse, C.L. Kosary, M. Krapcho, N. Neyman, R. Aminou, W. Waldron, J. Ruhl, N. Howlader, Z. Tatalovich, H. Cho, A. Mariotto, M.P. Eisner, D.R. Lewis, K. Cronin, H.S. Chen, E.J. Feuer, D.G. Stinchcomb, and B.K. Edwards (eds.), Bethesda, MD. Based on November 2009 SEER data submission, posted to the SEER web site, 2010. http://seer.cancer.gov/csr/1975_2007/ (accessed September 9, 2009), See Tables 4.7 and 4.8. 8 Rena Kass, Anne T. Mancino, Arlan L. Rosenbloom, V. Suzanne Klimberg, and Kirby I. Bland, Chapter 3: “Breast Physiology: Normal and Abnormal Development and Function,” and Victor G. Vogel, Chapter 16: “Epidemiology of Breast Cancer,” in The Breast: Comprehensive Management of Benign and Malignant Disease, eds. Kirby I. Bland and Edward M. Copeland III, 3rd ed. (Philadelphia: Saunders, 2003), 43-63, 341-354. 9 Bernardino Ramazzini with J. Corona, De morbis artificum diatriba (Venice, 1743), as cited in Mats Lambe, “Reproductive Factors,” in Breast Cancer Epidemiology, ed. Christopher E. Li (Springer, 2009), 120. 10 As developed later in the paper, women who have a spontaneous abortion (miscarriage) in their first trimester are unlikely to have had the breast tissue change associated with a normal pregnancy. 2 offer lifelong protection against breast cancer.11 Molecular biologists have determined that progenitor cells, or stem cells, in the breast do not become terminally differentiated (reach their full potential growth, or mature) until they have undergone pregnancy and have lactated.12 It has also been determined that these progenitor cells are lower in number in parous women and the number of these cells is related to breast cancer risk.13 It is only after 32 weeks’ gestation that elevated levels of pregnancy hormones allow sufficient maturation of cancer-resistant breast tissue to occur. Therefore, whether a pregnancy ends before 32 weeks with a premature birth, a second-trimester spontaneous abortion (that is, a miscarriage),14 or an induced abortion, a woman’s risk of breast cancer is increased.15 After a full-term pregnancy, only about 10 to 30 percent of a mother’s breast tissue remains susceptible to forming cancer.16 With each pregnancy a woman has subsequent to her first, her risk of breast cancer will decrease another 10 percent.17 However, the longer a woman waits to have her first full-term pregnancy, the higher is her risk of breast cancer, as her immature, cancer-vulnerable breast tissue is exposed to carcinogens for a longer duration. This period of time between menarche (the first menstrual cycle) and a pregnancy is termed the “susceptibility window,” as the breast is most adversely affected by carcinogens during that period.18 A long susceptibility window accounts for the transient (but statistically significant) rise in breast cancer risk that occurs in women who delay their first pregnancy until after age 30.19 During her susceptibility                                                              11 Jose Russo, Gabriela A. Balogh, Irma H. Russo, and the Fox Chase Cancer Center Hospital Network Participants, “Full-Term Pregnancy Induces a Specific Genomic Signature in the Human Breast,” Cancer Epidemiology, Biomarkers and Prevention 17, no. 1 (January 2008): 51-66. I. Verlinden, N. Güngör, K. Wouters, J. Janssens, J. Raus, and L. Michiels, “Parity-Induced Changes in Global Gene Expression in the Human Mammary Gland,” European Journal of Cancer Prevention 14 (2005): 129-137. 12 Werner Boecker, Stefanie Weigel, Walter Heindel, and Petra Stute, “The Normal Breast,” in Preneoplasia of the Breast: A New Conceptual Approach to Proliferative Breast Disease, ed. W. Boecker (Munich: Elsevier Saunders, 2006), 1-28. 13 S. Choudhury et al., “Molecular Profiling of Human Mammary Gland Links Breast Cancer Risk to a p27(+) Cell Population with Progenitor Characteristics,” Cell Stem Cell 13 (2013): 117-130.  14 Najmeh Tehranian, M. Amelbaraez, R. Salke, and S. Faghihzadeh, “The effect of abortion on the risk of breast cancer” (Iranian study presented at a conference at McMaster University, 2006). http://www.nursinglibrary.org/vhl/handle/10755/163877 (accessed April 29, 2013). 15 L.J. Vatten, P.R. Romundstad, D. Trichopoulos, and R. Skjærven, “Pregnancy Related Protection Against Breast Cancer Depends on Length of Gestation,” British Journal of Cancer 87 (2002): 289-290. Mads Melbye, Jan Wohlfahrt, A.-M.N. Andersen, Tine Westergaard, and Per Kragh Andersen, “Preterm Delivery and Risk of Breast Cancer,” British Journal of Cancer 80 (1999): 609-613. 16 J. Russo, Y.-F. Hu, X. Yang, and I. Russo, Chapter 1: “Developmental, Cellular, and Molecular Basis of Human Breast Cancer,” Journal of the National Cancer Institute Monographs 27 (2000): 22. See also Jose Russo and Irma H. Russo, “Development of the Human Mammary Gland,” in The Mammary Gland, eds. M. Neville and C. Daniel (New York: Plenum Publishing Corporation, 1987). 17 Mats Lambe, Chung-cheng Hsieh, Hsiao-wei Chan, Anders Ekbom, Dimitrios Trichopoulos, and Hans-Olov Adami, “Parity, Age at First and Last Birth, and Risk of Breast Cancer: A Population-Based Study in Sweden,” Breast Cancer Research and Treatment 38 (1996): 305-311. 18 F.M. Biro and M.S. Wolff, Chapter 2: “Puberty as a Window of Susceptibility,” in Environment and Breast Cancer, ed. J. Russo (New York: Springer, 2011), 29-36. 19 Note that women who delay first birth until age 25 or later have, relative to nulliparous women, a marginally statistically significantly increased risk of diagnosis at age 30. See Mats Lambe, Chung-cheng Hseih, Dimitrios Trichopoulos, Anders Ekbom, Maria Pavia, and Hans-Olov Adami, “Transient increase in the risk of breast cancer after giving birth,” New England Journal of Medicine 331 (1994): 5-9. 3 window, a woman may have developed a mutation or a cancer cell that the proliferation phase of her pregnancy would cause to grow. Hence, a woman who is pregnant and chooses abortion to end her pregnancy will deny herself the risk-lowering effects of a full-term pregnancy and will either remain childless or delay pregnancy, both of which increase her risk of premenopausal breast cancer at a rate of 5 percent per year of delay.20 These also put her at risk of premature delivery before 32 weeks,21 which would double her breast cancer risk.22 However, abortion itself poses an independent risk of breast cancer; that risk is the subject of this review. We have endeavored to make the present review comprehensive. We have drawn on the literature and relevant medical texts to explain breast physiology and the epidemiologic studies that deny or point to a link between induced abortion and breast cancer, and we make recommendations for further research. What follows immediately is a review of the biological changes in breast tissue over a woman’s lifetime and during pregnancy. Thereafter, we review and critique the research available and its evaluation by academics and relevant scientific organizations. We then review two sets of guidelines for establishing causation in epidemiological studies and conclude with research recommendations. II. Developmental biology affirms the induced abortion- breast cancer link In the sections to follow, we will address the development of the breast over the lifetime, the development of breast cancer, and the changes that arise in the breast during pregnancy and lactation. We also discuss the occurrence of miscarriage, premature delivery, induced abortion, and full-term pregnancy, and the risk of or protection against breast cancer that these reproductive events provide. As we show, the developmental biology of changes in the breast that occur during puberty and during a normal pregnancy supports the existence of an independent link between induced abortion and breast cancer.                                                              20 Françoise Clavel-Chapelon and Mariette Gerber, “Reproductive Factors and Breast Cancer Risk,” Breast Cancer Research and Treatment 72, no. 2 (2002): 107-115. 21 P. Shah and J. Zao, on behalf of Knowledge Synthesis Group of Determinants of Preterm/LBW Births, “Induced Termination of Pregnancy and Low Birthweight and Preterm Birth: A Systematic Review and Meta- Analyses,” British Journal of Obstetrics and Gynaecology 116, no. 11 (2009): 1425-1442. Hanes M. Swingle, Tarah T. Colaizy, M. Bridget Zimmerman, and Frank H. Morriss, “Abortion and Risk of Subsequent Preterm Birth: A Systematic Review and Meta-Analyses,” Journal of Reproductive Medicine 54 (2009): 95-108. 22 Mads Melbye, Jan Wohlfahrt, A.-M.N. Andersen, Tine Westergaard, and Per Kragh Andersen, “Preterm Delivery and Risk of Breast Cancer,” British Journal of Cancer 80 (1999): 609. C.C. Hsieh, J. Wuu, M. Lambe, D. Trichopoulos, H.O. Adami, and A. Ekbom, “Delivery of Premature Newborns and Maternal Breast Cancer Risk,” The Lancet 353 (1999): 1239. 4 A. Breast development Lobule growth. An infant is born with Type 1 lobules under the nipple-areola complex. (A lobule is a unit of breast tissue comprised of a milk duct with surrounding mammary [milk] glands, which are both composed of individual breast cells.) After puberty, females will develop more Type 1 lobules. Some Type 1 lobules will become Type 2 lobules after puberty as the breasts enlarge, at which point the breast contains a mixture of approximately 75 percent Type 1 lobules and 25 percent Type 2 lobules. Type 1 and Type 2 lobules are vulnerable to cancer. During the first half of pregnancy, the proliferation phase, Type 1 and Type 2 lobules increase in number. By week 20 of a 40-week (full-term) pregnancy, the breast has doubled in volume. The number of lobules in the breast increase through a decrease in the amount of breast stroma, or connective tissue, around the lobules. During the second half of pregnancy (after week 20), the differentiation phase, these immature, cancer-vulnerable Type 1 and Type 2 lobules begin to mature into cancer- resistant Type 4 lobules. Type 4 lobules are capable of producing the milk, or colostrum, the baby will need. After 32 weeks of pregnancy, sufficient Type 4 lobules have developed that a mother is protected against breast cancer, and she begins to incrementally gain the benefit of risk reduction that will maximize at 40 weeks. By the end of a normal pregnancy, 70 to 90 percent of the mother’s breast is composed of cancer-resistant Type 4 lobules. After birth and after a mother has lactated and breastfed (or should she choose not to breastfeed), Type 4 lobules regress to Type 3 lobules, which retain the epigenetic changes that protect against the development of cancer. This epigenetic change involves the “down-regulation” or “switching off” of lobule reproduction DNA, which thereafter stays permanently switched off and thereby protects against cancer.23 A woman’s risk of breast cancer will decrease an additional 10 percent with each subsequent pregnancy.24 This observed additional reduction in risk may be due to increased breastfeeding among these women, fewer lifetime menstrual cycles, and more anovulatory postpartum cycles (that is, postpartum cycles that do not produce an egg) with lower estrogen exposure, all known to reduce risk. Therefore, the woman who has a full-term pregnancy obtains lifelong benefits from the epigenetic changes it produces in the breast cells and gains even more risk reduction with additional births and breastfeeding.25                                                              23 A “down-regulated” gene is turned off; an “up-regulated” gene is turned on. A human’s cells all contain the same DNA. Turning different genes on or off (epigenetics) produces different kinds of cells. (For example: A liver cell and a skin cell contain the same DNA, but different genes in each cell are up-regulated and down-regulated, which is why some cells are liver cells and others are skin cells.) 24 Mats Lambe, Chung-cheng Hsieh, Hsiao-wei Chan, Anders Ekbom, Dimitrios Trichopoulos, and Hans-Olov Adami, “Parity, Age at First and Last Birth, and Risk of Breast Cancer: A Population-Based Study in Sweden,” Breast Cancer Research and Treatment 38 (1996): 305-311. 25 V. Beral, D. Bull, R. Doll, R. Peto, G. Reeves, Collaborative Group on Hormonal Factors in Breast Cancer, “Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50,302 women with breast cancer and 96,973 women without the disease,” The Lancet 360 (2002):187-195. 5 After menopause, Type 3 lobules morph into what appear to be Type 1 lobules microscopically; however, the epigenetic changes which have afforded cancer resistance remain. Figure 1: Lobule Development before, during, and after Pregnancy Table 1: Progression of Lifetime Breast Development26 Breast development State of breast lobule development After puberty 75 percent Type 1 and 25 percent Type 2 lobules After conceiving Increase in Type 1 and Type 2 lobules At 20 weeks’ gestation Absolute number of Type 1 and Type 2 lobules has greatly increased while stromal27 breast tissue has decreased as the breast has doubled in volume; maturation into Type 4 lobules commences At 32 weeks’ gestation Sufficient Type 1 and Type 2 lobules have matured into Type 4 lobules that the mother has a lowered risk of breast cancer At 40 weeks’ gestation 70 to 90 percent of the breasts are cancer-resistant Type 4 lobules After weaning Type 4 lobules stop milk production and regress to Type 3 lobules, which have permanent epigenetic changes that protect against cancer After menopause Type 3 lobules change morphologically into what appear to be Type 1 lobules; however, their genes do not change in their up- or down-regulation, so risk reduction is maintained Lobular structure. Again, a lobule is a unit of breast tissue comprised of a milk duct with surrounding mammary (milk) glands, which are both composed of individual breast cells.                                                              26 The microbiology of breast development is still not fully settled, and there are not enough data (there are no thousands of samples) to be totally certain about the progression of lobule stage development, especially regarding differentiation into lobules Type 3 and Type 4. These developmental changes are not written in stone and will be clarified slowly, because there are risks associated with performing biopsies on pregnant and lactating women (e.g., complications such as milk duct fistulae). 27 Stroma is the tissue of the breast that is neither milk ducts nor glands. 6 The ductules which surround the terminal end, or milk, duct become the glands where milk is produced.28 Each type of lobule has varying numbers of ductules, which become the milk-producing glands during lactation. These lobules are different morphologically (i.e., in their shape) as well as metabolically (e.g., in their doubling time). Figure 2: Lobule Types and their Structures Ductules become milk-producing glands during lactation Lobular hormone sensitivity. Type 1 lobules have a greater number of estrogen and progesterone receptors in their cells’ nuclei than Type 2 lobules do. Type 2 lobules have significantly more of these receptors than Type 3 lobules. Stimulation of these estrogen and progesterone receptors causes breast cell growth through mitosis (cell division). The more receptors a breast cell has, the more sensitive and reactive it is to hormone levels. Pregnancy (as well as monthly menstrual cycles), which is characterized by elevated estrogen and progesterone levels, causes breast growth. As stated above, the breast doubles in volume by 20 weeks of pregnancy by reducing the amount of connective tissue (stroma) and increasing the numbers of lobules it contains.29 By 32 weeks, full differentiation to more cancer-resistant Type 4 lobules, capable of producing colostrum, has occurred in sufficient numbers that the breast is protected against cancer.30 All these structural and metabolic changes are regulated by genes turning on and off (epigenetic switches). We know exactly which genes have been “turned off” and “turned on” (down-regulated and up-regulated) throughout a full term of pregnancy31 under the influence of pregnancy hormones.                                                              28 The ductules come off the duct draining the lobule called the “terminal end duct.” The small terminal ducts drain into larger and larger milk ducts, or lactiferous ducts. These lactiferous ducts transport milk to the lactiferous sinuses, which are just below the nipple. 29 This is the result of hCG stimulation of estrogen and progesterone production in the first half of pregnancy, which, in turn, stimulates breast cell division. 30 The mother’s hPL levels rise three times higher than her prolactin levels by the end of pregnancy, which enables full differentiation to Type 4 lobules. 31 Jose Russo, Gabriela A. Balogh, Irma H. Russo, and the Fox Chase Cancer Center Hospital Network Participants, “Full-Term Pregnancy Induces a Specific Genomic Signature in the Human Breast,” Cancer Epidemiology, Biomarkers and Prevention 17, no. 1 (January 2008): 51-66. I. Verlinden, N. Güngör, K. Wouters, J. Janssens, J. Raus, and L. Michiels, “Parity-Induced Changes in Global Gene Expression in the Human Mammary Gland,” European Journal of Cancer Prevention 14 (2005): 129-137. 7 Concurrent fetal development. During this time of maternal breast maturation, a parallel development is occurring in the fetus. During the fourth week of pregnancy, the milk streak (area of future breast tissue development) of the embryo forms. Development of the mammary ridge follows in the fifth week, and invasion into the chest wall takes place between the seventh and eighth weeks. (In humans, only two areas of the milk ridge persist in forming breasts.) The solid cords of epithelial cells in the fetal chest wall become canaliculized, or hollow, at 32 weeks, thereby developing the milk ducts and glands of the newly forming fetal breasts.32 B. Breast cancer formation Cancer formation and breast cell growth. Cells grow through mitosis, or cell division. Before a single cell divides into two cells, it must make a complete copy of its DNA. The process of cell division occurs during the cell cycle, which also includes a resting phase after the synthesis of new DNA and other cell structures; thus, if errors are made when DNA is copied, they can be repaired during this resting phase. Table 2: Lobular Morphology, Cancer Vulnerability, and Structure Type Morphology Type of cancer Structural and metabolic differences of of of lobules that forms from lobules lobule lobules Type 1 Average 11 Ductal cancers • Highest number of estrogen and ductules per (which are progesterone receptors in the cells lobular unit approximately 85 • Highest rate of cell proliferation percent of all (marked by Ki67 protein) breast cancers), • Shortest DNA doubling time arising in milk ducts33 Type 2 Average 47 Lobular cancers • Approximately half the number of ductules per (which are estrogen and progesterone receptors as lobular unit approximately 15 Type 1 lobules percent of all • One third of the cell proliferation breast cancers), marker Ki67 protein of Type 1 lobules arising in milk • A shorter DNA doubling time than glands Type 3 lobules Type 3 Average 81 Cancer-resistant • Negligible numbers of estrogen and ductules per progesterone receptors lobular unit • Less than one tenth of the cell proliferation marker Ki67 protein of Type 1 and Type 2 lobules                                                              32 Jose Russo and Irma H. Russo, “Development of the Human Mammary Gland,” in The Mammary Gland, eds. M. Neville and C. Daniel (New York: Plenum Publishing Corporation, 1987). 33 A lobule has a milk duct and glands. The gland makes the milk, and the milk duct collects the milk. Under the microscope, a pathologist can determine whether a cancer is ductal or lobular carcinoma. Ductal cancers start in the ducts of Type 1 lobules, and lobular cancers start in the glands of Type 2 lobules. 8 • Type 4 lobules regress to Type 3 after cessation of breastfeeding Type 4 Average 81 Cancer-resistant • Absence of proliferation34 ductules per • Lobules produce and contain colostrum lobular unit (early milk) or mature milk in their glands Cancer formation. The time that mitosis (splitting from one into two cells) and DNA synthesis take is the cell’s doubling time. The cells of each type of lobule have different doubling times and other measures of metabolic activity, such as cellular proliferation (identified by the level of the Ki67 protein it contains).35 A short doubling time may result in more mutations, because the cell has a shorter resting phase (i.e., a shorter time for DNA repair). Cancer develops from a mutation or damage done to a cell’s DNA. Genotoxins (such as radiation or some chemicals) can directly damage DNA and cause a mutation without cell division. Unless the mutation occurs in a critical gene (such as p53, a tumor suppressor gene which normally detects mutations in DNA at the G1 checkpoint, and in which a mutation permits many cancer-producing mutations to pass the G1 checkpoint unchanged), most cancers form after several mutations have built up in a cell over a number of years. After mitosis, any mutated daughter cells will undergo mitosis again with a greater chance of more mutations forming. Lobules’ cancer vulnerability. The shorter the time in which the DNA doubles, or copies itself, the greater is the risk of forming a mutation or cancer cell. Type 1 and Type 2 lobules copy their DNA more quickly than Type 3 lobules, so they are more cancer-vulnerable. Again, when DNA is copied quickly and the cell cycle is shorter, there is less time in the resting phase (when DNA mistakes are repaired), so more mutations are passed on. There is not enough time to repair all of them before the cell divides. Eighty-five percent of breast cancers arise in Type 1 lobules (ductal cancers). Ten to 15 percent of all breast cancers arise in Type 2 lobules (lobular cancers). Almost all cancers arise in Type 1 and Type 2 lobules. Estrogen and progesterone production stimulates this DNA reproduction and cell growth. As noted earlier, Type 1 lobules have the most estrogen and progesterone receptors, and Type 2 lobules have fewer than Type 1. Type 3 lobules have negligible numbers of estrogen and progesterone receptors. The differing quantities of receptors in the lobules’ cells’ nuclei correspond to levels of cell proliferation.                                                              34 Type 4 lobules do not proliferate, as they are terminally differentiated and producing milk. 35 R. Dickson and J. Russo, Chapter 2: “Biochemical Control of Breast Development,” in Diseases of the Breast, eds. Jay R. Harris, Marc E. Lippman, Monica Morrow, and C. Kent Osborne, 2nd ed. (Philadelphia: Lippincott Williams & Wilkens, 2000), 16-18. 9 Cancer detection. A breast cell’s doubling time accounts for the time a tumor takes to become large enough to be clinically detectable through an imaging study, such as a mammogram, or by a physical exam through palpation, or feeling the breast. On average, one microscopic breast cancer cell takes eight to 10 years to grow through mitosis into a tumor mass (lump) one centimeter in diameter.36 This is why cancer caused by an induced abortion37 may not become detectable for eight to 10 years. Types of cancer. There are invasive and in situ cancers of both the milk ducts and milk glands. This classification depends upon the origin and location of the cancer cells. The receptors of the cancer cells are also examined and reflect their genetic phenotype. When cancer cells form in the milk ducts or glands but do not penetrate the outer layer of the duct or gland (the basement membrane), a cancer is said to be an in situ cancer. Less than half of these ductal in situ cancers can be felt as a “lump,” but half develop calcifications, which can be detected on mammograms. These cancers are curable, because they have not penetrated the basement membrane where the lymphatic channels or blood vessels are located; they cannot spread to other parts of the body. In situ cancers can develop in the milk duct and form ductal carcinomas in situ. They may also arise in the milk glands and form lobular carcinomas in situ. Invasive cancers have penetrated the basement membrane and can spread throughout the body, becoming metastatic and life-threatening. Most invasive cancers start as in situ cancers, and most (85 percent) of these are ductal cancers. Breast cancer treatment has become more effective by routinely analyzing the cancer cells for estrogen (ER), progesterone (PR), and Her 2 neu (HER2) receptors. These receptors can be positive (+) or negative (-). They are also assessed by how proliferative the cells are by measuring the protein Ki67. Breast cancers are sometimes described by the array of genes that are expressed. At present there are four major subtypes: luminal A (ER+ and/or PR+, HER2-, low Ki67), luminal B (ER+ and/or PR+, HER2+ or HER2- with high Ki67), triple-negative/basal- like (ER-, PR-, HER2-), and HER2 type (ER-, PR-, HER2+). C. Changes during pregnancy and breastfeeding Embryo stimulation of hormone production. The embryo (or blastocyst) has a direct role in stimulating the mother’s own protective biological processes. A mother’s breasts enlarge very soon after conception, becoming sore and tender, one of the first signs of pregnancy. This occurs because the embryo’s production of hCG (human                                                              36 J. Gershon-Cohen, S.M. Berger, and Herbert S. Klickstein, “Roentgenography of breast cancer moderating concept of ‘biologic predeterminism,’” Cancer 16, no. 8 (August 1963): 961-964. 37 An examination of the timing in which breast cancer is statistically most likely to manifest itself after a woman obtains an induced abortion (around a decade to 14 years thereafter, with a seemingly diminished risk of manifestation 15 or more years after the abortion is procured) seems to indicate that induced abortion is itself a carcinogenic experience and is not merely an event that weakens a woman’s defenses against breast cancer. See Appendix D for further explanation. 10