scholarly journals Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4685
Author(s):  
Raghuveer Kavarthapu ◽  
Rajakumar Anbazhagan ◽  
Maria L. Dufau
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Signaling Pathways ◽  
Endocrine Therapy ◽  
Target Genes ◽  
Breast Tumors ◽  
Epidermal Growth ◽  
Her2 Signaling

Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB) signaling pathways activated by prolactin (PRL) and epidermal growth factor (EGF), have a major role in the mammary gland development and in the etiology of breast cancer, respectively. ER+ breast tumors comprise up to 75% of all breast cancers and 10% of these are HER2+. Elevated levels of PRLR in breast tumors, high circulating levels of PRL and increased expression of ERBB1/2 in patients that become resistant to endocrine therapy have shown to be associated with higher risk of cancer progression. In this review, we examine the role of crosstalk between PRLR and ERBB1/2 signaling pathways in the activation of unliganded ERα, cyclin-D1 and other oncogenic factors (MYC, FOS, JUN) in breast cancer. PRL/PRLR and EGF/EGFR induces phosphorylation of ERα through activation of MEK/MAPK and PI3K/AKT signaling pathways. PRL in breast cancer cells via PRLR/JAK2 can also induce phosphorylation of ERBB2/HER2, which in turn activates the downstream RAS/MEK/ERK pathway required for ERα phosphorylation. EGFR, independent of PRL/PRLR, can activate STAT5 indirectly via c-SRC and drive the expression of target genes involved in cell proliferation and survival. The crosstalk between PRLR and HER2, where PRL induces HER2 signaling can be an alternative route for ERα activation to induce transcription of PRLR and other ER target genes. We believe that overexpression of EGFR/HER2 and PRLR in breast tumors could maximize the actions of their ligands, and further induce cell proliferation promoting malignancy. This could also explain the resistance to endocrine therapy resulting in tumor growth.

scholarly journals Insulin-Like Growth Factor and Epidermal Growth Factor Signaling in Breast Cancer Cell Growth: Focus on Endocrine Resistant Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Kallirroi Voudouri ◽  
Aikaterini Berdiaki ◽  
Maria Tzardi ◽  
George N. Tzanakakis ◽  
Dragana Nikitovic
Keyword(s):  
Breast Cancer ◽  
Growth Factors ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Signaling Pathways ◽  
Endocrine Therapy ◽  
Insulin Like Growth Factor ◽  
Resistant Disease ◽  
Cancer Pathogenesis ◽  
Epidermal Growth

Breast cancer is the most common type of cancer for women worldwide with a lifetime risk amounting to a staggering total of 10%. It is well established that the endogenous synthesis of insulin-like growth factor (IGF) and epidermal growth factor (EGF) polypeptide growth factors are closely correlated to malignant transformation and all the steps of the breast cancer metastatic cascade. Numerous studies have demonstrated that both estrogens and growth factors stimulate the proliferation of steroid-dependent tumor cells, and that the interaction between these signaling pathways occurs at several levels. Importantly, the majority of breast cancer cases are estrogen receptor- (ER-) positive which have a more favorable prognosis and pattern of recurrence with endocrine therapy being the backbone of treatment. Unfortunately, the majority of patients progress to endocrine therapy resistant disease (acquired resistance) whereas a proportion of patients may fail to respond to initial therapy (de novo resistance). The IGF-I and EGF downstream signaling pathways are closely involved in the process of progression to therapy resistant disease. Modifications in the bioavailability of these growth factors contribute critically to disease progression. In the present review therefore, we will discuss in depth how IGF and EGF signaling participate in breast cancer pathogenesis and progression to endocrine resistant disease.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

2022 ◽  
Author(s):  
Erica L. Mayer ◽  
Christian Fesl ◽  
Dominik Hlauschek ◽  
Laura Garcia-Estevez ◽  
Harold J. Burstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Human Epidermal Growth Factor ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

scholarly journals Overcoming endocrine resistance in hormone receptor–positive breast cancer

2018 ◽  
Vol 25 ◽  
pp. 18 ◽  
Author(s):  
A. AlFakeeh ◽  
C. Brezden-Masley
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Signalling Pathways ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Endocrine therapy, a major modality in the treatment of hormone receptor (hr)–positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)–targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways—most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and PIK3CA mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.

Epidermal growth factor receptor expression in breast cancer: Association with response to endocrine therapy

1994 ◽  
Vol 29 (1) ◽  
pp. 117-125 ◽  
Author(s):  
Robert I. Nicholson ◽  
Richard A. McClelland ◽  
Julia M. W. Gee ◽  
David L. Manning ◽  
Peter Cannon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endocrine Therapy ◽  
Growth Factor Receptor ◽  
Receptor Expression ◽  
Epidermal Growth

scholarly journals Recent advances in the treatment of hormone receptor-positive/human epidermal growth factor 2-positive advanced breast cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110133
Author(s):  
Huimin Lv ◽  
Min Yan ◽  
Zefei Jiang
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Advanced Breast ◽  
Research Progress ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive (HR+/HER2+) advanced breast cancer is a special subtype of cancer with unique features. Major guidelines recommend that combination therapy containing anti-HER2 therapy (e.g., trastuzumab and pertuzumab) should be applied as the first-line treatment for HER2+ advanced breast cancer, regardless of HR status. Endocrine therapy could be relegated to patients who cannot tolerate chemotherapy or as a post-chemotherapy empirical maintenance strategy. Previous studies have shown that the HR pathway interacts with the HER2 pathway, and the HR and HER2 pathways of endocrine therapy combined with targeted therapy can effectively avoid tumor resistance. Therefore, the combination of endocrine and targeted therapies is the preferred treatment plan for HR+/HER2+ patients to replace chemotherapy. In this review, we will discuss research progress regarding endocrine therapy combined with anti-HER2 therapy in patients with advanced breast cancer, to provide more evidence for clinical practice and broader perspectives for related research. In the future, we hope there will be more studies on HR+/HER2+ advanced breast cancer to elucidate the optimal and appropriate treatment for these patients.

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