Effect of infertility treatment and pregnancy-related hormones on breast cell proliferation in vitro

Abstract

background: Breast cancer development involves a series of mutations in a heterogeneous group of proto-oncogenes/tumor suppressor genes that alter mammary cells to create a microenvironment permissive to tumorigenesis. Exposure to hormones during infertility treatment may have a mutagenic effect on normal mammary epithelial cells, high-risk breast lesions and early-stage breast cancers. Our goal was to understand the association between infertility treatment and normal and cancerous breast cell proliferation. methods: MCF-10A normal mammary cells and the breast cancer cell lines MCF-7 [estrogen receptor (ER)-positive, well differentiated]and HCC 1937 (ER-negative, aggressive, BRCA1 mutation) were treated with the weak ER activator clomiphene citrate and hormones that are increased during infertility treatment. Direct effects of treatment on cell proliferation and colony growth were determined.results: While clomiphene citrate had no effect on MCF-10A cells or MCF-7 breast cancer cells, it decreased proliferation of HCC 1937 versus untreated cells (P ¼ 0.003). Estrogen had no effect on either MCF-10A or HCC 1937 cells but, as expected, increased cell proliferation (20-100 nM; P ≤ 0.002) and colony growth (10-30 nM; P , 0.0001) of MCF-7 cells versus control. Conversely, progesterone decreased both proliferation (P ¼ 0.001) and colony growth (P ¼ 0.01) of MCF-10A cells, inhibited colony size of MCF-7 cells (P ¼ 0.01) and decreased proliferation of HCC 1937 cells (P ¼ 0.008) versus control. hCG (100 mIU/ml) decreased both proliferation (P ≤ 0.01) and colony growth (P ≤ 0.002) of all three cell lines.conclusions: Although these data are preclinical, they support possible indirect estrogenic effects of infertility regimens on ER-positive breast cancer cells and validate the potential protective effect of pregnancy-related exposure to hCG.

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer

“…35,36 In 2 recent in vitro studies, FSH, luteinizing hormone, and clomiphene did not increase breast cell proliferation, whereas estrogen increased cell proliferation of estrogen receptor-positive breast cancer cells. 37,38 Progesterone and hCG both decreased breast cell proliferation. 38 A case-control study reported a decreased risk of breast cancer after hCG given during infertility or weight loss treatments.…”

“…37,38 Progesterone and hCG both decreased breast cell proliferation. 38 A case-control study reported a decreased risk of breast cancer after hCG given during infertility or weight loss treatments. 39 In our study, women with the highest number of IVF cycles had the lowest risk of breast cancer.…”

Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

“…11,12 Breast cancer cells and tumors respond to progestins through an unknown mechanism, which generally act as pro-survival and proliferative factors. 7,[13][14][15][16][17] Progestins may also promote angiogenesis and assist in immunoevasion, both of which contribute to tumor survival and growth.…”

Impact of infertility regimens on breast cancer cells: follicle-stimulating hormone and luteinizing hormone lack a direct effect on breast cell proliferation in vitro

“…Thus, increased production of estrogens during infertility treatment may promote the malignant potential of key cell cycle regulatory proteins in mammary epithelium (15). Our prior work showed no effect of E2 on ER− MCF-10A and HCC 1937 cells in vitro, with doses of E2 comparable to those observed during COH cycles, whereas an expected increase in proliferation was observed when MCF-7 ER+ cells were treated with escalating does of estrogen (16,17). For breast cancer patients with ER+ lesions, the proliferative effect of E2 on malignant cells is well established.…”

“…Estradiol (E2), a known cell cycle mitogen and promoter of breast cell proliferation (13–15), is elevated to supraphysiologic levels during COH for IVF. Previous work assessing the effects of E2 in estrogen receptor-positive (ER+) breast cancer cells in vitro showed a proliferative effect at treatment levels similar to those encountered during IVF cycles (16). Furthermore, escalating doses of E2 correlated with increased ER+ breast cancer cell proliferation.…”