The Ecology of Breast Cancer The Promise of Prevention and the Hope for Healing By Ted Schettler MD, MPH

October 2013 This work is licensed under a Creative Commons Attribution Non-Commerical NoDerivs 3.0 Unported License.

Chapter 1

Toward a systems perspective of breast cancer

B

reast cancer is an ancient disease. Its recorded history dates back to ancient Egypt (3000-2500 BCE). Early documents describe what tumors looked like as they surfaced and progressed.1,2 Recorded speculations about their origins appear much later. Hippocrates and others espoused a humoral theory, thinking that imbalances among four bodily fluids— blood, yellow bile, black bile, and phlegm—caused this to happen. Galen (130-c.200 CE) subscribed to Hippocrates’ bodily humors theory, persuaded that he saw breast cancer more often in melancholy (literally, “black bile”) women who were creative, kind, and considerate. Some thought they saw cancer more generally in women who were anxious, depressed, or grieving.3 For Galen and many who followed, breast cancer was a systemic disorder and not confined to a single part of the body. In the 17th century, Italian physician Ramazzini saw that “tumors of this sort [breast cancer] are found more often in nuns than in any other women. In my opinion, these tumors are not due to amenorrhea, but rather to the celibate life led by these nuns.”4,5 Some theories proposed that trauma or lymphatic or milk duct blockage was involved. But with the invention of the microscope and emerging understanding of a cellular basis of anatomical structures, cancer cells became visible, and breast cancer began to be seen as a more localized disease. New anesthetic techniques aided a dramatic increase in surgery and, for decades, the radical mastectomy, pioneered by William Halsted, dominated breast cancer treatment. Halsted believed that removing enough tissue and precision to avoid spreading cancer cells during surgery led to the best chances of cure.

The Ecology of Breast Cancer

6

In the late 19th century Scottish surgeon George Beatson reported that removal of the ovaries in several of his patients caused remission of inoperable breast cancer.6,7 Hormones had not yet been characterized, but Beatson saw lactation prolonged in farm animals after their ovaries were removed. “Lactation is at one point perilously near becoming a cancerous process if it is at all arrested,” he said.8 During ensuing years, scientists identified estrogen and other hormones.9 Surgeons sometimes added removal of the ovaries, adrenals, and pituitary glands to breast cancer treatment. Thus, the emphasis on the cellular basis of cancer began to include consideration of the general hormonal environment influencing tumor growth. In his 1966 Nobel acceptance speech, Charles Huggins, a cancer biologist who studied the hormone dependency of various cancers, observed, “The net increment of mass of a cancer is a function of the interaction of the tumor and its soil. Self-control of cancers results from a highly advantageous competition of host with his tumor. There are multiple factors which restrain cancer - enzymatic, nutritional, immunologic, the genotype, and others. Prominent among them is the endocrine status, both of tumor and host.”10 Huggins saw cancer not just as a disease of aberrant cells but as one that requires a host environment favoring tumor growth. Despite this understanding, with the development of techniques of molecular biology that have enabled more detailed study of cells and sub-cellular parts, many cancer biologists continued to focus their attention on the cancerous cell.

Cancer: A disease of cells or tissues? Scientists have long been aware that cancer development is a multi-stage, multi-factorial phenomenon. The models they use generally describe tumor initiation, promotion, progression, and metastasis. In a widely-cited paper, Hanahan and Weinberg listed six hallmarks of cancer generally having to do with cancer cells—their response to various signals, evading growth suppressors, activating invasion and metastasis, resisting cell death, and so on.11 Recently, they added tumor promoting inflammation to their framework,12 but basically they privilege the original mutated cancer cell as most important, with secondary contributions from the nearby tissue microenvironment. This is the somatic mutation theory of carcinogenesis. Another view holds that cancer is a tissue-based disease.13,14 It proposes that changes in the tissue environment that normally keep cellular proliferation in check are central to the origins of cancer. Advocates of this view point out that cellular proliferation is the default state of most cells and gene mutations and changes in gene expression are common even within cells that do not develop into cancer. Interactions with the surrounding tissue are essential for modulating these activities and their effects. Experimental evidence in laboratory ani-

7

Toward a systems perspective of breast cancer

mals, for example, shows that tumors developing in the ductal epithelial cells of mammary glands depend on exposure of the surrounding stroma to a carcinogen and not just epithelial cell exposure.15 Moreover, using the same animal model, these authors showed that epithelial cancer cells introduced into normal stroma could form normal, non-cancerous mammary ducts.16 That is, the cancer cells could revert to normal. Thus, this theory holds, stromal-epithelial interactions in the tissue environment are more important than events in a mutated cell in the development and progression of cancer. From this it follows that an integrated approach, whereby cancer causation occurs in all directions, namely bottom-up, top-down, and reciprocally, will best illuminate the complexity of cancer and opportunities for prevention. These contrasting views differ with respect to the level of organization most appropriate for understanding the origins of cancer. One emphasizes the primary role of aberrant cells, while the other features an altered tissue environment and the importance of multi-level interactions.

Breast cancer and the more general environment The importance of the more general environment in the origins and progression of breast cancer becomes clear after looking at evidence discussed in later chapters. We know that latent, undiagnosed breast cancer develops over many years—in some cases over decades— and may be undetected during life. A review of seven autopsy studies reported invasive breast cancer in an average of 1.3 percent of 852 women ages 40-70 who had died from other causes and were not known to have breast cancer while alive.17 The number of tissue sections examined ranged from 9-275 per breast in five of the seven studies and was not described in two. Carcinoma in situ (CIS)* was reported in 8.9 percent on average. Highest percentages were reported in studies where the breasts of the deceased were examined more thoroughly. One of the studies included 110 consecutive autopsies of young and middle-aged women (ages 20-54), finding invasive breast cancer in two (1.8 percent) and CIS in twenty (18 percent).18

* There are two kinds of carcinoma in situ, ductal and lobular. Ductal carcinoma in situ (DCIS) refers to breast duct epithelial cells that have become “cancerous,” but still reside in their normal place. Lobular CIS (LCIS) refers to cells in the lobules that have undergone similar changes. In this setting cancerous means that there is an abnormal increase in the growth of the cells. CIS is nonlethal because it stays in place, but is important because it may progress to invasive breast cancer. However, some cases of CIS !"#$"%#&'"(')**#%"#+$,-*+,)#!+*)-*)#-$!#&')!+.%+$(#/0+.0#"$)*#/+11#-$!#/0)$#%0-%#2-3#0-&&)$#+*#!+45.61%7## 89:;#+*#."22"$13#5'*%#+!)$%+5)!#&"*6')?#-1%0"6(0#+%@*#$"%#"6%#"4 #%0)#=6)*%+"$7#A6%#%0+*#'-+*)*#-$#+2&"'%-$%#=6)*%+"$#-