Abstract
Resistance to hormonal therapy frequently occurs following successful treatment in breast cancer. The mechanism responsible for this acquired resistance is still unknown. It has been suggested that a hypoxic tumor microenvironment promotes malignant progression of cancer, i.e., hypoxia may promote estrogen-independent growth (a more malignant phenotype) of breast cancer. To clarify this hypothesis, the effects of hypoxia on the growth responses to hormonal agents and the expression levels of estrogen receptor (ER)-alpha and progesterone receptor (PgR) were investigated in two human breast cancer cell lines, ML-20 and KPL-1. The expression level of ER-alpha was significantly decreased by hypoxia (1% O(2)) in a time-dependent manner in both cell lines. Hypoxia also significantly reduced the growth-promoting effect of estradiol (E2) and the growth-inhibitory effects of an antiestrogen, ICI 182 780, and a progestin, medroxyprogesterone acetate, in both cell lines. In addition, hypoxia markedly suppressed the induction of PgR mRNA and protein by E2 in both cell lines. To clarify further the effect of hypoxia on ER-alpha expression, the expression levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a marker of hypoxia and ER-alpha were immunohistochemically examined in 36 breast cancer specimens. ER-alpha expression (both its proportion and intensity) was significantly lower in nuclear HIF-1 alpha-positive tumors than in negative tumors. These findings indicate that hypoxia down-regulates ER-alpha expression as well as ER-alpha function in breast cancer cells. These processes may lead to an acquired resistance to hormonal therapy in breast cancer.