Abstract
Epidemiological studies have indicated increased risk for breast cancer within 10 years of childbirth. Acute inflammation during mammary involution has been suggested to promote this parity-associated breast cancer. We report here that estrogen exacerbates mammary inflammation during involution. Microarray analysis shows that estrogen induces an extensive proinflammatory gene signature in the involuting mammary tissue. This is associated with estrogen-induced neutrophil infiltration. Furthermore, estrogen induces the expression of protumoral cytokines/chemokines, COX-2 and tissue-remodeling enzymes in isolated mammary neutrophils and systemic neutrophil depletion abolished estrogen-induced expression of these genes in mammary tissue. More interestingly, neutrophil depletion diminished estrogen-induced growth of ERα-negative mammary tumor 4T1 in Balb/c mice. These findings highlight a novel aspect of estrogen action that reprograms the activity of neutrophils to create a pro-tumoral microenvironment during mammary involution. This effect on the microenvironment would conceivably aggravate its known neoplastic effect on mammary epithelial cells.
Highlights
Epidemiological studies have indicated increased risk for breast cancer within 10 years of childbirth
The microarray data were validated by real-time PCR (RT-PCR) analysis of a panel of 10 genes that are involved in immune function or cell adhesion (S100a8, S100a9, Ccl[6], Ccl[9], Cxcl[1], Cxcl[2], Timp[1], Vcan, Cd44 and Anxa2) (Fig. 1b)
The known estrogen target genes Growth Regulation by Estrogen in Breast cancer 1 (Greb1), Amphiregulin (Areg), and Progesterone Receptor (Pgr) were not present in the list of estrogen-regulated genes by microarray analysis, these genes were found to be significantly up-regulated by Real Time PCR (RT-PCR) analysis (Fig. 1c)
Summary
Epidemiological studies have indicated increased risk for breast cancer within 10 years of childbirth. Acute inflammation during mammary involution has been suggested to promote this parity-associated breast cancer. Microarray analysis shows that estrogen induces an extensive proinflammatory gene signature in the involuting mammary tissue This is associated with estrogen-induced neutrophil infiltration. Neutrophil depletion diminished estrogen-induced growth of ERα-negative mammary tumor 4T1 in Balb/c mice. These findings highlight a novel aspect of estrogen action that reprograms the activity of neutrophils to create a pro-tumoral microenvironment during mammary involution. This effect on the microenvironment would conceivably aggravate its known neoplastic effect on mammary epithelial cells. The involvement of neutrophils in tumorigenesis during mammary involution has not been studied
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