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Estrogen withdrawal, increased breast cancer risk and the kras-variant

McVeigh, Terri P
; 
Jung, Song-Yi
; 
Kerin, Michael J
; 
Salzman, David W
; 
Nallur, Sunitha
; 
Nemec, Antonio A
; 
Dookwah, Michelle
; 
Sadofsky, Jackie
; 
Paranjape, Trupti
; 
Kelly, Olivia
... show 9 more
Identifiers
http://hdl.handle.net/10379/12853
https://doi.org/10.13025/29058
Repository DOI
10.1080/15384101.2015.1041694
Publication Date
2015-05-11
Keywords
breast cancer risk, estrogen withdrawal, kras-variant, multiple primary breast cancer, triple negative breast cancer, tumor biology, microrna-binding-site, women, epidemiology, polymorphism, mutations, receptor, therapy, cells
Type
Article
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Citation
McVeigh, Terri P; Jung, Song-Yi; Kerin, Michael J; Salzman, David W; Nallur, Sunitha; Nemec, Antonio A; Dookwah, Michelle; Sadofsky, Jackie; Paranjape, Trupti; Kelly, Olivia; Chan, Elcie; Miller, Nicola; Sweeney, Karl J; Zelterman, Daniel; Sweasy, Joann; Pilarski, Robert; Telesca, Donatello; Slack, Frank J; Weidhaas, Joanne B (2015). Estrogen withdrawal, increased breast cancer risk and the kras-variant. Cell Cycle 14 (13), 2091-2099
Abstract
The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42-37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.
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Publisher
Informa UK Limited
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Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)