The growth of female breast depends upon several hormones, the most important of which is estrogen. Estrogen governs the development of the ductal system of the breast whereas progesterone is responsible for the proper development of the lobular system.
Prolonged Exposure to Estrogen Can Cause Breast Cancer
It has been seen that prolonged exposure to estrogen can produce cancerous changes in the breast. This is because estrogen gets metabolized to produce substances which are genotoxic and mutagenic in nature. This, when combined with the tissue growth stimulation by estrogen, can result in initiation, promotion and progression of carcinogenesis.
Several conditions can result in a prolonged exposure to estrogen. It is well-known that menstruation raises the estrogen levels. A woman goes through an increased number of menstrual cycles in her reproductive phase of life in case she has menarche at an early age and a late menopause. This results in a greater cumulative exposure to estrogen. Similarly, the early irregular periods, immediately after menarche and the irregular periods just before menopause, are both associated with a disordered maturation of the corpus luteum. This causes insufficient production of progesterone and consequently, an environment rich in estrogen.
In women who conceive late, the condition is often a result of involuntary infertility. Here again, there is a disordered follicular maturation. This leads to a hormonal environment of estrogen sufficiency, along with the absence of the regular, cyclic increase in progesterone, associated with the normal menstrual cycles.
Historical Evidence to Prove That Breast Cancer Is Associated with Estrogen Levels
The earliest evidence which supports the link between estrogen and breast cancer was seen in 1713. At that time, it was noted that the nuns in Padua had an unusually high incidence of breast cancer. 129 years after this observation, a scientist named Rigoni Stern found that this association between nuns and breast cancer was probably due to Nulliparity (the condition of not bearing offspring). The nuns were three times more likely to develop breast cancer than women with children. Later on Schinzinger and then Beatson found that the growth of cancer is slower in postmenopausal women and an early menopause, either natural or attained through surgical means, offers protection against breast cancer. These observations further strengthened the association between exposure to estrogen and development of breast cancer.
Molecular Mechanism behind the Action of Estrogen in Breast Cancer
Estrogen promotes the growth of the cancer cells through its action on estrogen receptors present on the surface of the cancer cells. Besides, non receptor mediated effects of estrogen also play an important part in breast cancer development. This can be corroborated by the fact that aromatase inhibitors like letrozole, which block the synthesis of estrogen, have been found to be more effective in the treatment of breast cancer as compared to estrogen receptor blockers like tamoxifen which only block the action of estrogen, mediated through the receptors.
Body Fat Is an Important Source of Estrogen
The supply of estrogen to the body is through different sources in premenopausal and postmenopausal women. While ovaries are largely responsible for the production of estrogen in premenopausal women, they are replaced by other peripheral sites in postmenopausal women. Adipose tissue, or the body fat, is an important source of estrogen biosynthesis in postmenopausal women. It increases the level of estrogen circulating in the blood as well as local production of estrogen in the breast tissue and thus, promotes breast cancer in postmenopausal women. The adipose tissue, as well as the fat in the breast tissue, contains a set of enzymes called as “aromatase." These enzymes are responsible for converting the androgens, androstendione and testosterone, produced by the postmenopausal ovaries and adrenal glands into estrogens, estrone and estradiol, respectively. The aromatase present in the breast tissue can produce local estrogen which is ten times the level of estrogen present in the circulation. Aromatase inhibitors, which prevent the conversion of androgens into estrogen, form an important part of breast cancer therapy.
A meta-analysis of six studies showed that women who developed breast cancer had 15% more estrogen in their blood compared to women who did not develop the disease. Another meta-analysis of nine studies showed that women with high levels of circulating estrogen were twice more likely to develop breast cancer compared to women with lower levels of estrogen. The European Prospective Investigation into Cancer and Nutrition (EPIC) study showed that the total and free estradiol levels in postmenopausal women diagnosed with breast cancer had significantly increased from the levels three years before the diagnosis was made.
Relationship between Obesity and Estrogen Receptors
The estrogen receptors are of 2 types – alpha and beta. When saying about the estrogen receptor of a tumor, it is mainly in reference to the alpha estrogen receptors as they are associated with the proliferation of the breast tissue. The beta estrogen receptors, when present in the tumor, are associated with a favorable prognosis. A cancerous tumor of the breast has a high ER alpha to ER beta ratio.
The nature of tumors found in obese women is usually ER alpha positive. This is especially true for postmenopausal obese women. This corroborates the fact that obesity is associated with high levels of estrogen which promote the growth of cancer.
Estrogens Used in Hormone Replacement Therapy Can Also Lead to Breast Cancer
Hormonal replacement therapy leads to an increased level of estrogen in postmenopausal women. The level of serum estradiol found in postmenopausal women after estrogen replacement or transdermal estrogen are the same as those found in the follicular phase of premenopausal women.
Many studies have reported that longer the duration of use of hormone replacement therapy, higher the chance of developing breast cancer. Investigators from Oxford University did a meta-analysis of 51 epidemiologic studies involving more than 52,000 women with breast cancer and more than 100,000 women without breast cancer. After taking all the confounding factors into consideration, the researchers concluded that the risk of breast cancer increased by 2.3% for each year of use of hormone replacement therapy. Estrogen without progestins was the major hormone used in these studies. It was deduced that there are six extra cases of breast cancer in women who use hormone replacement therapy after the age of 50 for duration of 10 years. It increases to 12 extra cases in women who take the therapy for 15 years.
What further proves that exogenous estrogen from the hormone replacement therapy is associated with breast cancer is the fact that mammography of such patients reveals a higher incidence of increased cell proliferation.
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