In 2002, a large clinical trial, the Women’s Health Initiative (WHI), found that HRT (Hormone Replacement Therapy) use increases the risk of breast cancer in postmenopausal women. Following these findings, many women stopped using HRT. The hormones, used in the WHI study, were estrogen and a progestin, a synthetic form of progesterone. Now, researchers, using a breast cancer rat model, found that both estrogen and progesterone have to be present for tumor growth to occur. Together, these two hormones increase a protein in the breast that causes both normal and tumor cells to grow.
Estrogen alone reduces the risk of breast cancer
Estrogen has been blamed for tumor growth of hormone receptor-positive cancers. To protect postmenopausal women from uterine cancers, HRT always includes a progestin. A reanalysis of the data from the large WHI trial, presented at the 33rd Annual CTRC-AACR San Antonia Breast Cancer Symposium in 2010, showed that when women use estrogen without a progestin, they are protected from breast cancer. In the WHI trial, only women without a uterus were given estrogen alone. The protective effect of estrogen alone was only found in women, who did not have a strong family history of breast cancer.
Progesterone increases breast cancer risk
Women who took both estrogen and progesterone had a greater risk of breast cancer in the WHI trial. Although the role of estrogen in hormone-dependent tumors has been well studied, less is known about the role of progesterone. Researchers studied the development of breast tumors in rats and cultured human breast cancer cells. They found that the growth of tumor cells was caused by an epidermal growth factor protein, called amphiregulin. The increase in amphiregulin and activation of the epidermal growth factor signaling pathway required both estrogen and progesterone. In the experiments, researchers used both progestins (synthetic molecules similar to progesterone) and natural progesterone with similar results. When the researchers used an epidermal growth factor receptor inhibitor, Iressa, to prevent amphiregulin from binding to its receptor, the tumors and tumor cells stopped growing.
Amphiregulin does not cause breast tumors; it causes quiescent tumors to grow. Estrogen and progesterone, via amphiregulin, promote hormone-dependent tumors to grow. Drugs that target the interaction between estrogen, progesterone, and the intracellular signaling pathways could combat hormone-dependent tumors, especially in premenopausal women who have high levels of endogenous estrogen and progesterone. The researchers write: ” These results indicate that mediators of cross talk between E [estrogen], P [progesterone], and EGFR [epidermal growth factor receptor] pathways may be considered relevant molecular targets for the therapy of hormone-dependent breast cancers, especially in premenopausal women” (Kariagina, A. et al.).
New strategies can be developed to treat a subset of postmenopausal women with estrogen alone to reduce their risk of breast cancer. However, because estrogen promotes blood clots that can lead to heart attacks or stroke, these risks have to be taken into account.
Kariagina, A. et al. Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal mammary gland and in hormone-dependent rat mammary cancers. Hormones and Cancer (2010) 1: 229