Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance

Arpino, Grazia; Weiss, Heidi L.; Lee, Adrian V.; Schiff, Rachel; Placido, Sabino De; Osborne, C. Kent; Elledge, Richard M.

doi:10.1093/jnci/dji249

Cited by 431 publications

(356 citation statements)

References 32 publications

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“…The luminal A has higher expression of hormone receptors and related genes and low expression of proliferative genes, while the luminal B has lower expression of the ER and higher expression of proliferative genes. Previous studies in breast cancer cell lines have in fact implicated HER1/HER2 signaling in lowering the expression of PgR and/or ER [29][30][31]. In particular, in the subgroup of patients with ER positive and PgR absent disease, hyperactive cross-talk between ER and growth factor signaling pathways, leading to a more aggressive course of the disease, was recently reported [32,33].…”

Section: Discussionmentioning

confidence: 99%

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

Colleoni

Bagnardi

Rotmensz

et al. 2008

Breast Cancer Res Treat

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Section: Discussionmentioning

confidence: 99%

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

Colleoni

Bagnardi

Rotmensz

et al. 2008

Breast Cancer Res Treat

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“…PRs are independent markers of breast cancer prognosis, irrespective of progestational status (60)(61)(62). Further, ER+/PR+ tumors clearly metastasize (63).…”

Section: Ligand-independent Pr Actionsmentioning

confidence: 98%

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

et al. 2007

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Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30 min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFα and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.

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“…Within ER-positive breast cancers, women with negative PR expression do worse than those expressing PR, but data are only of value for the postmenopausal population [8][9][10][11]. This is probably related to the fact that a negative PR status stands for alternative signaling through, for example, the epidermal growth factor pathway [12][13][14][15]. ER-positive/PR-negative tumors express higher levels of HER-1 and, especially, HER-2 and have more aggressive features than ER/PRpositive tumors [12,16].…”

Section: Introductionmentioning

confidence: 99%

“…This is probably related to the fact that a negative PR status stands for alternative signaling through, for example, the epidermal growth factor pathway [12][13][14][15]. ER-positive/PR-negative tumors express higher levels of HER-1 and, especially, HER-2 and have more aggressive features than ER/PRpositive tumors [12,16]. Overexpression of receptors for growth factors such as HER-2 has also been shown to play an important prognostic role, independent of lymph node status, tumor size, or ER-status [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors

Brouckaert

Pintens

Belle

et al. 2008

Breast Cancer Res Treat

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Introduction Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the shortterm disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype. Patients and methods Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 -(PPN), ER + PR -HER-2 -(PNN), ER + PR + HER-2 + (PPP), ER -PR -HER-2 -(NNN), ER -PR -HER-2 + (NNP), and ER + PR -HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy. Results Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI. Conclusion It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

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Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance

Cited by 431 publications

References 32 publications

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors

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