Breast Cancer: A Wider Angle View (Part 1)

Epigenetics and Aging (18)

(This post will serve as a prolog for the next one.)

The somatic mutation theory of cancer is a bottom-up view of the matter, typical of a geneticist mindset. Heretofore, my discussions of epigenetic landscapes, though not as genocentric, still focused exclusively on only what goes on inside a target cell. Here I will look at things from a wider angle. Epigenetic processes are notoriously subject to environmental influences, not just the intracellular environment but the extra cellular environment as well. To understand the epigenetic dimension, the bottom-up approach needs to be augment with a top-down perspective.

The extracellular environment is many layered, ultimately extending to factors outside of the human body, including social interactions. We don’t need to go that far out though for present purposes. Let’s start at the tumor level. Tumors are not just aggregations of cancerous cells; they are comprised of a motley assortment of cell types. These include immune cells, blood cells (red and white), fat cells, fibroblasts, noncancerous host cells and the cancerous host cells. The interactions of these heterogenous cells play an important role in cancer progression.

Mina Bissell (University of California, Berkeley), who is the hero of this story, recommends that we treat tumors as organs, with their own metabolism (10.1046/j.1432-0436.2002.700907.x). Tumor organs function in a larger metabolic context, most immediately, that of the surrounding epithelial tissue and stroma, as wells as the extracellular matrix, the stuff in the spaces between cells, and the medium through which cells chemically communicate. In stromal tissue there are lots of open spaces, hence lots of extracellular matrix. The epithelium and stroma, among other elements, constitutes what is known as the cancer microenvironment (https://europepmc.org/article/med/10197593).

Breast cancer, the subject of Bissell’s work, is the most frequently occurring cancer in women, and the leading cause of cancer-related deaths. Though much less common, breast cancer can also occur in men. There are many types of breast cancer, as measured by gene expression profiles. For simplicity, they are often classified in two distinct ways. By the type and locations of the cells in which it originates, or by the presence or absence of three types of receptors in those cells, estrogen, progesterone, HER2, or some combination. Those that lack all three are called triple negative. Breast cancers in which estrogen receptors are evident are the most common. They are generally treated through hormone therapies, including tamoxifen and its successors. These therapies are very effective, but breast cancers so treated have a high recurrence rate, due, it is assumed, to small populations of residual cells that are resistant to the drugs involved ( 33741974).

Before proceeding further, a few words about BRCA. The overall heritability of breast cancer is quite low. Inherited mutations in BRCA1 and BRCA2, however, significantly raise the risk of breast cancer, as well as ovarian cancer (and prostate cancer). These mutations are also associated with an earlier onset of breast cancer than is typical of an age-related disease. Mutations in these genes, however, are present in only 1-2% of breast cancers diagnosed each year (https://doi.org/10.1097/01.GIM.0000151155.36470.FF); for the rest we need to look elsewhere.

To investigate potential chemical therapies for any form of cancer the cancer cells are often cultivated as cell cultures in a lab. Traditionally, a single layer of cancerous cells is maintained. Though useful for identification of mutations, 2D cell cultures have their limitations because they poorly approximate what goes on in actual breasts. Bissell’s innovation was to make these cell cultures more like the environment of the breast itself. Early on, she recognized that it was crucial, in this regard, to culture the cells in three dimensions to simulate the way the cells would interact there. She was initially ridiculed for this approach. At one conference three eminent male scientists mocked her, banging the table and shouting 3D, 3D, 3D (https://doi.org/10.1016/j.cell.2020.03.028). Vindication arrived soon after when she was able to obtain milk proteins from mouse mammary cells so cultivated (https://doi.org/10.1073/pnas.91.26.12378).

But 3D cultures, were just the first step. To more closely approximate what occurs in the breast, she incorporated cells from the microenvironment, as well as the extracellular matrix. We now know that the microenvironment can inhibit or encourage tumor progression. As such, elements of the microenvironment are now viewed as potential targets of drug therapies (https://doi.org/10.1016/j.celrep.2020.107701. One important influence of the microenvironment is metabolic support or nonsupport of the tumor. Proliferating cells require lots of energy. Proliferation is a sine qua none of cancer cells. Logically, a good way to suppress tumors is to cut off their energy supply. Ultimately this energy is derived from the conversion of glucose to ATP (Adenosine triphosphate), the energy currency of all cells. Hence, any way to starve the tumor of glucose or its derivatives, should be therapeutic (10.1016/j.semcancer.2021.09.008). Though logical there was a lack of empirical evidence, until recently. Turned out the problem in finding this connection was the limitations of 2D cell cultures. When 3D cell cultures were employed, the repressive effects of glucose starvation on tumors became evident (10.1172/JCI63146).

In the next post in this series, I will adopt Bissell’s wide-angle approach in exploring how glucose changes the epigenetic landscape, not only in the breast cancer cells themselves but also in the cells of the breast tumor microenvironment.