Hypoxia Reduces Hormone Responsiveness of Human Breast Cancer Cells

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 (

BRCA1 tumours correlate with a HIF-1α phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression

“…In a multivariate analysis, HIF-1a was the only independent variable, which predicted ERa negativity. This is consistent with cell culture studies where intermittent hypoxia induces proteasome-dependent downregulation of ERa (Kurebayashi et al, 2001;Cooper et al, 2004;Yi et al, 2009). This is also supported by immunohistochemical studies on ERa-positive tumours where the geographic distribution of CAIX, a surrogate marker of hypoxia, corresponds to areas of tumour negative for ERa (Cooper et al, 2004).…”

Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

“…This is in concordance with earlier published data, 35 but apart from the association to the cell cycle, this could also indicate that HIF-1a expression is correlated to a certain type of breast cancer with proliferative features and frequent overexpression of cyclin E. 36,37 HIF-1a has not been previously explored in relation to treatment prediction in a randomised treatment trial, but one breast cancer cell line study has demonstrated that hypoxia induces tamoxifen-resistant growth. 24 In our study we could not confirm this link between hypoxia and tamoxifen response, and both HIF1a low and high tumours appeared to respond to tamoxifen treatment. Since there is a negative association between ER and HIF1a expression, the amount of ER-positive and HIF-1a high tumours was rather small in our study, which might have affected the results.…”

“…19 From studies of breast cancer cell lines, it appears that hypoxia also correlates to loss of ER expression [20][21][22][23] and that this may induce tamoxifenresistant growth. 24 Hormone independent growth is frequently caused by abnormalities in growth factor signalling pathways such as EGFR, HER2, MAPK-signalling via ERK1/2, or IGFR via PI3K, 25 all of which may be influenced by HIF-1a. HIF-1a has also been implicated as an independent prognostic marker in both lymph node-negative 26 as well as lymph node-positive breast cancers.…”

ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERα: a combination therapy potentially targeting hypoxic and dormant tumor cells

“…Initially, we treated hypoxic cells with tamoxifen (1.0 mM) for 48 h during hypoxic and normoxic conditions, whereupon the cell-cycle phase distribution was evaluated by flow cytometry. The anti-estrogen response differed substantially between normoxic and hypoxic samples, as partially detailed earlier (Kurebayashi et al, 2001). As illustrated in Figure 3a and b, there was an 18% increase in G 0 /G 1 cells in tamoxifen treated normoxic cells, after 48 h, but only a 9% G 0 /G 1 accumulation with tamoxifen during hypoxia (see Figure 3b, P-values were calculated using Student's ttest).…”