Estrogen is a key hormone influencing the growth and development of breast cancer, particularly in tumors expressing estrogen receptors (ER+). While estrogen doesn’t cause breast cancer, it can act locally within the breast tissue to stimulate the proliferation (growth and division) of cancer cells, playing a significant role in tumor development and progression.
Estrogen Receptor (ER) Binding: In Estrogen Receptor Positive (ER+) breast cancer, estrogen binds to ERs located inside the cancer cells. This binding triggers a series of events leading to the activation of genes involved in cell growth and survival.
The observation the 17b-estradiol (E2), the most potent estrogen levels are 10-fold higher in breast carcinoma tissue compared to plasma also supports the role for intra-tumoral estrogen synthesis. Recent studies have established that concentration gradients of aromatase expression occur within the breast, with the highest levels of expression occurring in sites next to a tumor. The enzyme aromatase, primarily expressed in the ovaries in premenopausal women and in peripheral tissues like adipose, (fat) tissue in postmenopausal women, is responsible for converting androgens, male hormones into estrogen. Normal breast adipose tissue maintains low levels of aromatase expression. In breast cancer, increased local aromatase activity within the tumor and surrounding tissue can lead to increased estrogen levels in the tumor microenvironment, further fueling Estrogen receptor positive, ER+ cell proliferation.
Estrogen can exert its effects locally through autocrine and paracrine mechanisms.
Autocrine: In this scenario, breast cancer cells themselves produce estrogen which then acts on their own estrogen receptors ERs to promote growth.
Paracrine: Estrogen produced by nearby cells in the tumor microenvironment, such as stromal cells or adipocytes, can act on the estrogen, ERs of breast cancer cells to stimulate their growth. This paracrine action of estrogen is particularly important in postmenopausal women, where local synthesis of estrogen in the breast tissue becomes a crucial factor.
Estrogen can also stimulate the expression of various growth factors and their receptors, like insulin-like growth factor (IGF-1) and epidermal growth factor receptor (EGFR). These growth factors activate intracellular signaling pathways (e.g., MAPK and PI3K/Akt) which can further promote breast cancer cell proliferation and contribute to endocrine resistance.
Estrogen primarily promotes cell proliferation by driving the progression of breast cancer cells through the cell cycle, particularly the G1 to S phase transition. It does this by activating genes like cyclin D and c-myc, which are essential regulators of cell cycle progression.
Understanding the local action of estrogen in breast cancer is crucial for the development and use of endocrine therapies, which aim to either reduce estrogen levels (e.g., aromatase inhibitors) or block ER action (e.g., tamoxifen or fulvestrant). However, resistance to these therapies remains a challenge, and further research into the molecular mechanisms of estrogen signaling and its interaction with other pathways is needed to develop more effective treatments,
