Nederlands Русский Breast Cancer.
Health Strategy.

Alternative therapy for breast cancer (#11).

Normalization of breast tissue.

Cancer is a disease associated with a violation of the organization of tissue and the interaction of individual cells. Uncontrolled cell growth is not enough to form cancer. Only when the architecture of normal tissue is disorganized can we say that the normal tissue has undergone a «neoplastic transformation».

The development of the tumor process in the mammary gland is preceded and accompanied by a number of local pathological changes that are associated with: latent inflammation; hyperplasia in the ducts; the appearance of hypoxic areas with increased extracellular acidity; accumulation of extracellular matrix and cells associated with the tumor; degradation of the vascular system and impaired fluid flow; increase in the volume of intercellular space; increased intratumoral pressure, etc.

We can directly or indirectly influence these processes, for example, by reducing the carcinogenic effect, reducing the inflammatory level, restoring hormonal balance, normalizing the acidity of the tissue,etc.

Characteristic features that distinguish the tumor microenvironment (TME) from the normal tissue environment (NTE) are presented in the table below. NTE usually suppresses cancer at an early stage of tumor development, while the effects of TME most often induce cancer. It can be assumed that if we can convert the characteristics of TME to NTE, then cancer cells in the tissue will be replaced by normal cells * *.

Tissue architecture
Tissue density
Cell nutrition
Oxygen level
Tissue acidity
pH 7,35
pH 6,7-7,1
Extracellular matrix
Chronic inflammation
Developed and organized
Immature and poorly organized
Tumor immunity
Not activated

The tumor microenvironment is the cellular environment in which the tumor exists. As you know, a tumor is not a homogeneous mass of cancer cells. It includes many other supporting cells, including cancer-associated fibroblasts, inflammatory immune cells, and blood and lymphatic endothelial cells. Together, this is held together by the extracellular matrix produced by fibroblasts and loaded with signaling molecules, secreted factors, and other elements.

Density of breast tissue. The mammary gland includes adipose, glandular and connective tissues. On a mammogram, they appear differently. Adipose tissue is radiologically less dense and appears darker, while glandular and connective tissues are more dense and appear lighter. Thus, the greater the content of epithelial cells, fibroblasts, collagen and extracellular matrix in the breast, the thicker and fatter the light web on mammography, the higher the percentage of mammographic breast density (MD).

Categories of mammographic density Enlarge Image

Breasts with increased tissue density not only make it harder to detect breast cancer on mammograms, but also increase the risk of breast cancer *. Women with a 75% increase in density have a 4-6 times greater risk of cancer than women without an increase in density * *. This is especially true for women without excess body fat *.

Three-quarters of women have increased mammographic breast density in their 30s and older. However, the widespread prevalence of increased breast density, despite the assurances of some doctors, does not mean the normality of this phenomenon, just as the widespread prevalence of overweight or hypertension does not mean normality. Most often, high density is observed in women 40-49 years old *. Breast tissue density naturally decreases with age, which reduces the risk of cancer, but women who continue to have high breast density are more likely to be diagnosed with breast cancer *.

Dense breast tissue is very strongly associated not only with morbidity but also with mortality from breast cancer *.

Many factors contribute to the increase in breast density. Some of them cannot be changed, such as high birth weight or being an Ashkenazi Jewish ethnic group. Other negative factors are modifiable. For example, hormonal factors: increased levels of estradiol *, reduced levels of free androgens (testosterone, androstenedione) *, the use of hormone replacement therapy (estrogen+progestin) *. The increase in breast density can be caused by some nutritional factors such as inadequate intake of vitamin D *, increased consumption of red meat, especially in adolescence *, alcohol * *, saturated fat *, high glycemic foods * *. Weight gain in adulthood is also associated with increased mammographic density *.

Compaction sites create favorable conditions for the future appearance of a tumor there, and a decrease in tissue density could reduce this risk. Women with already diagnosed breast cancer who were able to reduce mammographic density by more than 10% had a 55% lower risk of developing cancer on the opposite side of the breast compared to women whose density did not change or changed little from baseline *.

The reduction in tissue density is real. In one clinical trial, about 30% of patients with moderate to severe breast induration who took 3×100 mg of proanthocyanidins orally for 6 months were able to reduce the area of induration by more than half after radiation therapy compared with the placebo group *.

In another study, the use of an anti-inflammatory complex of boswellic acid, betaine (trimethylglycine) and myo-inositol for 6 months significantly reduced breast density in premenopausal women (60% in the experimental group versus 9% in the control group) *. This complex is available as a finished product (Eumastos®), where the daily capsule contains 200 mg of myo-inositol, 175 mg of betaine, 100 mg of N-acetyl-cysteine, 50 mg of boswellic extract (15 mg of boswellic acid), folic acid, vitamins В2, В6, В12. Taken 1 capsule per day. This complex also reduces the volume of fibroadenoma in young women *.

Long-term use of tamoxifen helps to reduce mammographic density * *; vitamin D (1'750-3'000 IU/day) * * * * * as well as inositol in combination with alpha-lipoic acid * may also slightly improve density values. Daily consumption of green tea is also associated with a lower percentage of mammographic density compared to abstaining from it *. In addition, mammographic breast density can be reduced to some extent by regular intake of aspirin *.

Mammographic density of the breast can also be reduced through dietary and lifestyle modifications, primarily by limiting the intake of sugar *, fat * * and animal protein *. Energy-dense food increases the density of breast tissue * – each unit of kcal/g increases the positive association by 25.9% *.

The largest statistical analysis, adjusted for age, body mass index, energy intake, and other confounding factors, showed a correlation between increased caloric intake and increased prevalence of high mammographic density: for every additional 500 cal/day, by 23%. It has also been found that an increase in olive oil consumption reduces the prevalence of high mammographic density: each increase in olive oil consumption by 22 g/day is 14%, while an increase in whole milk consumption, on the contrary, increases: each increase by 200 g/day – by 11% *.

Switching to a diet low in fat (~21% of total calories) and high in complex carbohydrates (~61% of total calories) for 2 years improves radiographic findings in women with mammographic density values greater than 50% of the breast *.

After 2 years of a low-fat, high-carbohydrate diet, there is a significant reduction in the area of induration, especially in menopausal women. In women who survived menopause during the 2-year follow-up period, the average decrease in area and percentage of density in the intervention group was, respectively, 11.0 cm2 and 11.0%, while in the control group – only 4.5 cm2 and 5. 2% respectively *.

Hardening of breast tissue may be caused by accumulation of extracellular matrix due to inflammation-associated fibrosis. Fibrosis and associated inflammation is a central factor in tumor progression.

The extracellular matrix, the main structural component of the tumor microenvironment, creates a favorable niche for cancer stem cells. The influence of the extracellular matrix extends to the acquisition by cells of the main features of cancer cells – loss of differentiation, insensitivity to apoptosis signals, changes in metabolism, continuous self-renewal, and genomic instability. In addition, the dense network of collagen in tumors significantly impairs the supply of cells and reduces the supply and effectiveness of therapeutic agents, especially nanoparticles and large molecules.

Some pharmaceuticals are indirectly antifibrotic even though fibrosis is not their direct target *. These are, among others, metformin, acetylsalicylic acid, simvastatin, propranalol, angiotensin, β-blockers, matrix metalloproteinase inhibitors and some others *.

Pentoxifylline (3×400 mg) in combination with vitamin E (3-4×100 mg) for 12 months can reverse radiation-induced fibrosis of breast tissue * * * *.

Losartan, a drug used to treat hypertension, inhibited the production of collagen by fibroblasts associated with breast carcinoma in mice. This increased the efficiency of intravenous administration of liposomal doxorubicin (doxil) *. The human equivalent dosage used in this study will be about 120 mg/day, which is close to the maximum prescription, and the human equivalent duration of use will be 1.5 years, which is acceptable only for hypertensive patients.

Tranilast inhibits fibroblast proliferation and TGF-β production* in vitro and reduces matrix stiffness when treated with doxorubicin *.

Retinoic acid in vitro inhibits fibroblast production of extracellular matrix and interleukin IL-6 *.

A number of natural substances in vitro also show some anti-fibrotic effect through various mechanisms * *:

anti-inflammatory mechanism:
- curcumin from the root of Turmeric (Curcuma longa),
- resveratrol from the skin of Red grapes (Grape),
- tanshinon IIA from the root of Sage (Salvia miltiorrhiza),
- berberine from the fruits of Barberry (Berberis),
- schisandrin B from the fruit of Magnolia berry (Schisandra chinensis),
- quercetin from the leaves of Ginkgo (Ginkgo biloba),
- emodin from the rhizome of Rhubarb (Rheum palmatum);

antimyofibroblastic mechanism:
- salvianolic acid from the root of Sage (Salvia miltiorrhiza),
- baicalin from the root of Skullcap (Scutellaria baicalensis),
- luteolin from the flowers of Japanese honeysuckle (Lonicera japonica),
- epigallocatechin gallate (EGCG) from green tea;

antimatrix mechanism:
- wogonin from the root of Skullcap (Scutellaria baicalensis),
- matrine and oxymatrine from the root of Sophora (Sophora),
- madecassoside from the leaves of Gotu kola (Centella asiatica),
- puerarin from the root of Kudzu (Puerariae),
- chlorogenic acid from the flowers Hibiscus (Hibiscus sabdariffa),
- silymarin from the seeds of Milk thistle (Silybum marianum).

Note that fibrosis is associated not only with acute inflammatory processes, but also with the aging process, and anti-fibrotic measures can, to a certain extent, improve tissue health.

Immunity in tumor tissue decreases significantly as the disease progresses. The main immune cell types present in TME include regulatory T-cells (Treg), myeloid suppressor cells (MDSC), tumor associated macrophages (TAM) and functionally impaired dendritic cells (DC).

Pathological interactions between cancer cells and the body's immune cells create an environment that allows cancer cells to evade immune surveillance, suppression, and destruction. Among the conditions that weaken the immune response of the body against the tumor, one can name increased local acidity of the tissue; metabolic competition between cancer cells and immune cells for glucose, glutamine and amino acids (arginine, tryptophan) *.


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