EOBRECA · Differential Roles of Estrogens in Obesity-mediated ER+ Breast Cancer Development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-09-01 → 2021-11-23
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
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Results in brief
Differential Roles of Estrogens in Obesity-mediated ER+ Breast Cancer Development
Breast cancer is the most common cancer and the leading cause of cancer death in women in the world, and risk thereof rises progressively after menopause. Obesity is associated with increased postmenopausal, but not premenopausal, breast cancer risk, particularly for estrogen receptor-positive (ER+) breast cancers, which represent over 70% of all breast cancer cases diagnosed. Importantly, after menopause estrogens are mostly produced in the adipose tissue. These observations suggest a link between the estrogenic milieu associated to menopausal status and obesity, with ER+ breast cancer. This Project investigates if main pre- and postmenopausal estrogens in circulation, estradiol (E2) and estrone (E1) respectively, have different biological functions. In addition, this work investigates if enzymes involved in E1 synthesis, have an oncogenic role in this disease, and could be a new marker for early diagnosis and patient prognosis, and a new therapeutic target for patient´s treatment. The social impact of this Research Project is based on its potential to reduce disease incidence, morbidity and mortality. In this regards, results obtained from this Project may demonstrate a different role of E2 and E1 in ER+ breast cancer biology; and serve to develop new Hormone Replacement Therapies (HRT) safest for postmenopausal women, reducing the incidence of this disease. Moreover, the identification of E1-synthesizing enzymes as new molecular markers for early disease detection, or even useful to identify subjects at high risk to develop ER+ breast cancer, could reduce significantly the morbidity and mortality of this disease. The main objective of this project is to better understand the roles of E1 and E2 on obesity-associated ER+ breast cancer development. We hypothesize that E1 plays a key role in the increased risk of developing ER+ breast cancer in obese postmenopausal women through a differential regulation of important molecular pathways in normal tissues than the effect demonstrated for E2. In addition, we hypothesize that high expression of enzymes that convert E2 into E1, have an oncogenic role in the development of this disease and may be a new marker and a new therapeutic target for ER+ breast cancer patients. After the completion of this project we have obtained several important conclusions: - Menopause, obesity and cancer increase inflammation in the breast tissue - Estrone stimulates and estradiol relieves obesity-mediated inflammation - Adipocytes from the breast tissue, specially thus from obese and postmenopausal women, induce inflammation and progression on breast cancer cells - Estrone, but not estradiol, activates metastatic programs in ER+ human epithelial cancer cells from the breast and cervix - Enzymes that convert estradiol into estrone play a key role in ER+ breast carcinogenesis, tumor growth and metastasis
Data: CORDIS, © European Union
Project objective
Observational studies indicate that obesity and the risk of developing estrogen receptor-positive (ER+) breast cancers has an inverse association in premenopausal women, but a positive association in post-menopausal women. Breast cancer risk rises steeply after menopause, when estradiol decreases markedly and estrone become the major serum estrogen. Adipose tissue express high levels of the enzyme aromatase, being the major site of estrogen synthesis after menopause. Obesity in postmenopausal women correlates with increased serum estrone levels. Obesity and higher estrone, but not estradiol, are correlated with increased risk of ER+ breast cancer in postmenopausal women. Obesity mediates a chronic inflammatory state through NF-kB pathway activation of pro-inflammatory cytokine expression. The chronic inflammatory milieu established in the obese adipose tissue may be associated to the increased risk of developing several cancer types, including postmenopausal ER+ breast cancer. It is known that estradiol inhibits NF-kB activation through different molecular mechanisms. However, the role of estrone in regulating the NF-kB pathway has not been studied yet. Notably, low intra-tumor expression of enzymes converting estrone into estradiol, and overexpression of enzymes that convert estradiol into estrone are both associated with a worse outcome in ER+ breast cancer patients.This proposal pursue to elucidate the role of estrone in the increased risk of developing ER+ breast cancer in obese postmenopausal women. We hope to determine the roles of estrone and estradiol in regulating NF-kB pathway in adipocytes and ER+ normal epithelial mammary cells. We will also determine if enzymes involved in estradiol to estrone conversion have an oncogenic role in the development of this disease. Data obtained from this work have the potential to identify new markers and therapeutic targets against ER+ breast cancers, and lead to the design of new strategies for its prevention.
Original text from CORDIS.
Participants
- UNIVERSIDAD DE GRANADA · GranadaCoordinatorSpain
Links
Data: CORDIS, © European Union