ORIGINAL ARTICLEEndocrine responsiveness: Understanding how progesterone receptor can be used to select endocrine therapy
Section snippets
Estrogen receptors in breast cancer
The importance of steroid hormones in breast cancer pathogenesis and progression has been known for decades and the roles of the cognate receptors for estrogen (ER) and progesterone (PR) as important predictive markers have been confirmed by numerous studies. Estrogen and its receptor are crucial for breast cancer development and they are successful targets for prevention and treatment.1, 2, 3, 4 All endocrine therapies for breast cancer target ER in one way or another. PR is important in the
Progesterone receptor and response to tamoxifen
Studies performed 25 years ago confirmed the value of ER as an important biomarker that predicted response to different kinds of endocrine therapy. When PR was identified as an ER-regulated gene, it was hypothesized as described earlier that ER+/PR+ tumors would be more responsive to endocrine therapy than ER+/PR− tumors. Retrospective studies of patients with metastatic disease, most receiving tamoxifen, supported this idea (Table 1).31 PR− tumors consistently respond less well to endocrine
Membrane-initiated ER signaling
In addition to the function of ER as a transcriptional regulator in the nucleus, growing evidence suggests that a small pool of ER is located outside the nucleus in the cytoplasm or in the plasma membrane. The binding of estrogen to this receptor activates signals that appear within minutes and are, therefore, too rapid to be explained by a transcriptional mechanism.49 This membrane ER can modulate activities through several signaling pathways normally thought to be regulated by growth factors
Clinical implications
If the biology suggested by these laboratory studies is mirrored in breast tumors in patients, then it might be expected that ER+ tumors overexpressing HER2 would have reduced PR levels compared with those tumors not overexpressing HER2. Several clinical reports do suggest that high GF receptor content is associated with loss of PR.27, 69, 71, 72 Looking at this question from the opposite perspective, ER+ tumors lacking PR might be expected to express high levels of GF receptors such as IGF-1
Acknowledgments
This work was supported in part by a breast cancer SPORE Grant (P50 CA 50183), and a Komen Foundation Postdoctoral Fellowship (PDF0403061).
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Estrogen and progesterone signalling in the normal breast and its implications for cancer development
2018, Molecular and Cellular EndocrinologyCitation Excerpt :Moreover, the use of HRT and oral contraceptives (and particularly when synthetic progestins are included in these formulations (Asi et al., 2016; Li et al., 2012)) is associated with a higher risk of breast cancer, directly implicating exogenous hormone use in the etiology of breast carcinogenesis (Bhupathiraju et al., 2016). However, perhaps paradoxically, the presence of steroid hormone receptors (which is observed in up to 75% of breast tumours) marks a positive prognosis in breast cancer patients, and their expression remains the single most important predictive marker for endocrine responsiveness (Osborne et al., 2005). While the expression of ER and PR are important indicators, they are not definitive predictors of prognosis, as molecular profiling has identified subgroups within ER+PR+ tumours with widely different prognoses, for example, the Luminal B subgroup of ER+PR+tumours with high proliferation and poor prognosis (Tran and Bedard, 2011).
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