Nature Aging: tumors in patients over 70 converted estrone to estradiol more actively

Nature Aging: tumors in patients over 70 converted estrone to estradiol more actively

On July 27, Nature Aging published a study of hormone-dependent breast cancer in older women. The researchers compared blood and tumor tissue from 115 patients, a model using aged rats, and organoids, which are three-dimensional cultures grown from tumors.

In patients aged 70 years and older, estrone, a less active form of estrogen, predominated in plasma. In tumor cells, the enzyme HSD17B7 can convert estrone into estradiol, which activates the estrogen receptor and supports cell division. In hormone-dependent tumors, this receptor is one of the factors that drives growth.

In the study by Carlton and colleagues, tumors from patients over 70 contained more HSD17B7 RNA. Higher RNA levels were associated with a higher intratumoral ratio of estradiol to estrone. Systemic estrone and local estradiol production formed a single measurable pathway.

The researchers tested this part of the pathway in organoids derived from tumors in older patients. An HSD17B7 inhibitor reduced estradiol production, the activity of estrogen-responsive genes, and the proportion of cells in S-phase, when a cell copies its DNA before division.

Tumors from older patients contained more CCL2, a signaling protein that attracts monocytes, which are precursors of macrophages. The medium in which the organoids were grown induced human monocytes to develop into macrophages expressing the markers CD206 and PD-L1. Fulvestrant, which degrades the estrogen receptor, combined with an antibody against CCL2, reduced this shift.